Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, Adachi H, Fujiwara K, Okabe M, Suzuki T, Nunoki K, Sato E, Kakyo M, Nishio T, Sugita J, Asano N, Tanemoto M, Seki M, Date F, Ono K, Kondo Y, Shiiba K, Suzuki M, Ohtani H, Shimosegawa T, Iinuma K, Nagura H, Ito S, Matsuno S (2001) LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology 120:1689–1699

Abramovitch S, Dahan-Bachar L, Sharvit E, Weisman Y, Bentov A, Brazowski E, Reif S (2011) Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats. Gut 60:1728–1737

Abshagen K, Eipel C, Kalff JC, Menger MD, Vollmar B (2007) Loss of NF-kappaB activation in Kupffer cell-depleted mice impairs liver regeneration after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 292:G1570–G1577

Abshagen K, Eipel C, Kalff JC, Menger MD, Vollmar B (2008) Kupffer cells are mandatory for adequate liver regeneration by mediating hyperperfusion via modulation of vasoactive proteins. Microcirculation 15:37–47

Abu-Absi SF, Friend JR, Hansen LK, Hu WS (2002) Structural polarity and functional bile canaliculi in rat hepatocyte spheroids. Exp Cell Res 274:56–67

Abu-Absi SF, Hansen LK, Hu WS (2004) Three-dimensional co-culture of hepatocytes and stellate cells. Cytotechnology 45:125–140

Adams DH, Ju C, Ramaiah SK, Uetrecht J, Jaeschke H (2010) Mechanisms of immune-mediated liver injury. Toxicol Sci 115:307–321

Adams RM, Wang M, Crane AM, Brown B, Darlington GJ, Ledley FD (1995) Effective cryopreservation and long-term storage of primary human hepatocytes with recovery of viability, differentiation, and replicative potential. Cell Transpl 4:579–586

Afshari CA, Hamadeh HK, Bushel PR (2011) The evolution of bioinformatics in toxicology: advancing toxicogenomics. Toxicol Sci 120(Suppl 1):S225–S237

Agarwal S, Holton KL, Lanza R (2008) Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells 26:1117–1127

Agarwal R, Macmillan-Crow LA, Rafferty TM, Saba H, Roberts DW, Fifer EK, James LP, Hinson JA (2011) Acetaminophen-induced hepatotoxicity in mice occurs with inhibition of activity and nitration of mitochondrial manganese superoxide dismutase. J Pharmacol Exp Ther 337:110–116

Aithal GP, Ramsay L, Daly AK, Sonchit N, Leathart JB, Alexander G, Kenna JG, Caldwell J, Day CP (2004) Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 39(5):1430–1440

Akazawa Y, Gores GJ (2007) Death receptor-mediated liver injury. Semin Liver Dis 27:327–338

Akita H, Suzuki H, Hirohashi T, Takikawa H, Sugiyama Y (2002) Transport activity of human MRP3 expressed in Sf9 cells: comparative studies with rat MRP3. Pharm Res 19:34–41

Akiyama TE, Baumann CT, Sakai S, Hager GL, Gonzalez FJ (2002) Selective intranuclear redistribution of PPAR isoforms by RXR alpha. Mol Endocrinol 16:707–721

Alexandre E, Viollon-Abadie C, David P, Gandillet A, Coassolo P, Heyd B, Mantion G, Wolf P, Bachellier P, Jaeck D, Richert L (2002) Cryopreservation of adult human hepatocytes obtained from resected liver biopsies. Cryobiology 44:103–113

Alexopoulos LG, Saez-Rodriguez J, Cosgrove BD, Lauffenburger DA, Sorger PK (2010) Networks inferred from biochemical data reveal profound differences in toll-like receptor and inflammatory signaling between normal and transformed hepatocytes. Mol Cell Proteomics 9:1849–1865

Alfirevic A, Pirmohamed M (2010) Drug induced hypersensitivity and the HLA complex. Pharmaceuticals 4

Alison MR (2005) Liver stem cells: implications for hepatocarcinogenesis. Stem Cell Rev 1:253–60

Alison MR, Islam S, Lim S (2009) Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J Pathol 217:282–298

Allen MP, Tildersley DJ (1987) Computer simulation of liquids. Oxford Science, Oxford

Allen JW, Bhatia SN (2003) Formation of steady-state oxygen gradients in vitro: application to liver zonation. Biotechnol Bioeng 82:253–262

Allen JW, Khetani SR, Bhatia SN (2005) In vitro zonation and toxicity in a hepatocyte bioreactor. Toxicol Sci 84:110–119

Almeida CA, Martin AM, Nolan D, Lucas A, Cameron PU, James I, Phillips E, Mallal S (2008) Cytokine profiling in abacavir hypersensitivity patients. Antivir Ther 13:281–288

Alpini G, Phillips JO, Vroman B, Larusso NF (1994) Recent advances in the isolation of liver cells. Hepatology 20:494–514

Alpini G, Glaser S, Baiocchi L, Francis H, Xia X, Lesage G (2005) Secretin activation of the apical Na + -dependent bile acid transporter is associated with cholehepatic shunting in rats. Hepatology 41:1037–1045

Alvarez-Sanchez R, Montavon F, Hartung T, Pahler A (2006) Thiazolidinedione bioactivation: a comparison of the bioactivation potentials of troglitazone, rosiglitazone, and pioglitazone using stable isotope-labeled analogues and liquid chromatography tandem mass spectrometry. Chem Res Toxicol 19:1106–1116

Aly HA, Domenech O (2009) Cytotoxicity and mitochondrial dysfunction of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in isolated rat hepatocytes. Toxicol Lett 191:79–87

Aly HH, Oshiumi H, Shime H, Matsumoto M, Wakita T, Shimotohno K, Seya T (2011) Development of mouse hepatocyte lines permissive for hepatitis C virus (HCV). PLoS One 6:e21284

Amacher DE (2012) The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert Opin Drug Metab Toxicol 8:335–347

Amann T, Maegdefrau U, Hartmann A, Agaimy A, Marienhagen J, Weiss TS, Stoeltzing O, Warnecke C, Scholmerich J, Oefner PJ, Kreutz M, Bosserhoff AK, Hellerbrand C (2009) GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis. Am J Pathol 174:1544–1552

Ananthanarayanan M, Ng OC, Boyer JL, Suchy FJ (1994) Characterization of cloned rat liver Na(+)-bile acid cotransporter using peptide and fusion protein antibodies. Am J Physiol 267:G637–G643

Andersen ME, Birnbaum LS, Barton HA, Eklund CR (1997) Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation. Toxicol Appl Pharmacol 144:145–155

Anderson ARA, Chaplain MAJ, Rejniak KA (eds) (2007) Single-cell based models in biology and medicine. Birkhäuser, Basel, Switzerland

Andrade RJ, Lucena MI, Alonso A, Garcia-Cortes M, Garcia-Ruiz E, Benitez R, Fernandez MC, Pelaez G, Romero M, Corpas R, Duran JA, Jimenez M, Rodrigo L, Nogueras F, Martin-Vivaldi R, Navarro JM, Salmeron J, de la Cuesta FS, Hidalgo R (2004) HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease. Hepatology 39:1603–1612

Andrade RJ, Agúndez JA, Lucena MI, Martínez C, Cueto R, García-Martín E (2009) Pharmacogenomics in drug induced liver injury. Curr Drug Metab 10(9):956–970

Andrews E, Armstrong M, Tugwood J, Swan D, Glaves P, Pirmohamed M, Aithal GP, Wright MC, Day CP, Daly AK (2010) A role for the pregnane X receptor in flucloxacillin-induced liver injury. Hepatology 51:1656–1664

Andrews E, Daly AK (2008) Flucloxacillin-induced liver injury. Toxicology 254:158–163

Angelin B, Bjorkhem I, Einarsson K, Ewerth S (1982) Hepatic uptake of bile acids in man. Fasting and postprandial concentrations of individual bile acids in portal venous and systemic blood serum. J Clin Invest 70:724–731

Angrish MM, Jones AD, Harkema JR, Zacharewski TR (2011) Aryl hydrocarbon receptor-mediated induction of Stearoyl-CoA desaturase 1 alters hepatic fatty acid composition in TCDD-elicited steatosis. Toxicol Sci 124(2):299–310

Aninat C, Piton A, Glaise D, le Charpentier T, Langouet S, Morel F, Guguen-Guillouzo C, Guillouzo A (2006) Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos 34:75–83

Antherieu S, Chesne C, Li R, Camus S, Lahoz A, Picazo L, Turpeinen M, Tolonen A, Uusitalo J, Guguen-Guillouzo C, Guillouzo A (2010) Stable expression, activity, and inducibility of cytochromes P450 in differentiated HepaRG cells. Drug Metab Dispos 38:516–525

Anzai N, Ichida K, Jutabha P, Kimura T, Babu E, Jin CJ, Srivastava S, Kitamura K, Hisatome I, Endou H, Sakurai H (2008) Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem 283:26834–26838

Aoyama K, Yoshinari K, Kim HJ, Nagata K, Yamazoe Y (2009) Simultaneous expression of plural forms of human cytochrome P450 at desired ratios in HepG2 cells: adenovirus-mediated tool for cytochrome P450 reconstitution. Drug Metab Pharmacokinet 24:209–217

Apte U, Thompson MD, Cui S, Liu B, Cieply B, Monga SP (2008) Wnt/beta-catenin signaling mediates oval cell response in rodents. Hepatology 47:288–295

Apte U, Zeng G, Thompson MD, Muller P, Micsenyi A, Cieply B, Kaestner KH, Monga SP (2007) beta-Catenin is critical for early postnatal liver growth. Am J Physiol Gastrointest Liver Physiol 292:G1578–G1585

Aravalli RN, Cressman EN, Steer CJ (2012) Hepatic differentiation of porcine induced pluripotent stem cells in vitro. Vet J

Archer S, Li TT, Evans AT, Britland ST, Morgan H (1999) Cell reactions to dielectrophoretic manipulation. Biochem Biophys Res Commun 257:687–698

Arikura J, Kobayashi N, Okitsu T, Noguchi H, Totsugawa T, Watanabe T, Matsumura T, Maruyama M, Kosaka Y, Tanaka N, Onodera K, Kasai S (2002) UW solution: a promising tool for cryopreservation of primarily isolated rat hepatocytes. J Hepatobiliary Pancreat Surg 9:742–749

Asgari S, Moslem M, Bagheri-lankarani K, Pournasr B, Miryounesi M, Baharvand H (2011) Differentiation and transplantation of human induced pluripotent stem cell-derived hepatocyte-like cells. stem cell rev

Ashby J, Brady A, Elcombe CR, Elliott BM, Ishmael J, Odum J, Tugwood JD, Kettle S, Purchase IF (1994) Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis. Hum Exp Toxicol 13(Suppl 2):S1–S117

Atzori L, Poli G, Perra A (2009) Hepatic stellate cell: a star cell in the liver. Int J Biochem Cell Biol 41:1639–1642

Au JS, Navarro VJ, Rossi S (2011) Review article: Drug-induced liver injury–its pathophysiology and evolving diagnostic tools. Aliment Pharmacol Ther 34:11–20

Auth MK, Okamoto M, Ishida Y, Keogh A, Auth SH, Gerlach J, Encke A, McMaster P, Strain AJ (1998) Maintained function of primary human hepatocytes by cellular interactions in coculture: implications for liver support systems. Transpl Int 11(Suppl 1):S439–S443

Aydinlik H, Nguyen TD, Moennikes O, Buchmann A, Schwarz M (2001) Selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of beta-catenin-mutated mouse liver tumors. Oncogene 20:7812–7816

Baba T, Touchi A, Ito K, Yamaguchi Y, Yamazoe Y, Ohno Y, Sugiyama Y (2002) Effects of serum albumin and liver cytosol on CYP2C9- and CYP3A4-mediated drug metabolism. Drug Metab Pharmacokinet 17:522–531

Baccarelli A, Giacomini SM, Corbetta C, Landi MT, Bonzini M, Consonni D, Grillo P, Patterson DG, Pesatori AC, Bertazzi PA (2008) Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin. PLoS Med 5:e161

Bachmann K, Byers J, Ghosh R (2003) Prediction of in vivo hepatic clearance from in vitro data using cryopreserved human hepatocytes. Xenobiotica 33:475–483

Bacon BR, O’grady JG, Di bisceglie AM, Lake JR (2006) Comprehensive clinical hepatology. Elsevier Health Sciences. ISBN:0-323-03675-9

Badagnani I, Castro RA, Taylor TR, Brett CM, Huang CC, Stryke D, Kawamoto M, Johns SJ, Ferrin TE, Carlson EJ, Burchard EG, Giacomini KM (2006) Interaction of methotrexate with organic-anion transporting polypeptide 1A2 and its genetic variants. J Pharmacol Exp Ther 318:521–529

Bader A, Knop E, Kern A, Boker K, Fruhauf N, Crome O, Esselmann H, Pape C, Kempka G, Sewing KF (1996) 3-D coculture of hepatic sinusoidal cells with primary hepatocytes-design of an organotypical model. Exp Cell Res 226:223–233

Badmann A, Keough A, Kaufmann T, Bouillet P, Brunner T, Corazza N (2011) Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage. Cell Death Dis 2:e171

Badolo L, Rasmussen LM, Hansen HR, Sveigaard C (2010) Screening of OATP1B1/3 and OCT1 inhibitors in cryopreserved hepatocytes in suspension. Eur J Pharm Sci 40:282–288

Badolo L, Trancart MM, Gustavsson L, Chesne C (2011) Effect of cryopreservation on the activity of OATP1B1/3 and OCT1 in isolated human hepatocytes. Chem Biol Interact 190:165–170

Bai J, Cederbaum AI (2004) Adenovirus mediated overexpression of CYP2E1 increases sensitivity of HepG2 cells to acetaminophen induced cytotoxicity. Mol Cell Biochem 262:165–176

Bain DL, Heneghan AF, Connaghan-Jones KD, Miura MT (2007) Nuclear receptor structure: implications for function. Annu Rev Physiol 69:201–20

Baines CP (2011) The mitochondrial permeability transition pore and the cardiac necrotic program. Pediatr Cardiol 32:258–262

Bajt ML, Cover C, Lemasters JJ, Jaeschke H (2006) Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Toxicol Sci 94:217–225

Bajt ML, Farhood A, Lemasters JJ, Jaeschke H (2008) Mitochondrial B\ax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther 324:8–14

Bajt ML, Knight TR, Lemasters JJ, Jaeschke H (2004) Acetaminophen-induced oxidant stress and cell injury in cultured mouse hepatocytes: protection by N-acetyl cysteine. Toxicol Sci 80:343–349

Baker M, Parton T (2007) Kinetic determinants of hepatic clearance: plasma protein binding and hepatic uptake. Xenobiotica 37:1110–34

Baker SD, Verweij J, Cusatis GA, van Schaik RH, Marsh S, Orwick SJ, Franke RM, Hu S, Schuetz EG, Lamba V, Messersmith WA, Wolff AC, Carducci MA, Sparreboom A (2009) Pharmacogenetic pathway analysis of docetaxel elimination. Clin Pharmacol Ther 85:155–163

Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B (1990) Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249:912–915

Baker TK, Carfagna MA, Gao H, Dow ER, Li Q, Searfoss GH, Ryan TP (2001) Temporal gene expression analysis of monolayer cultured rat hepatocytes. Chem Res Toxicol 14:1218–1231

Baker TK, Kwiatkowski AP, Madhukar BV, Klaunig JE (1995) Inhibition of gap junctional intercellular communication by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat hepatocytes. Carcinogenesis 16:2321–2326

Bakker J, Lin X, Nelson WG (2002) Methyl-CpG binding domain protein 2 represses transcription from hypermethylated pi-class glutathione S-transferase gene promoters in hepatocellular carcinoma cells. J Biol Chem 277:22573–22580

Ballestero MR, Monte MJ, Briz O, Jimenez F, Gonzalez-San Martin F, Marin JJ (2006) Expression of transporters potentially involved in the targeting of cytostatic bile acid derivatives to colon cancer and polyps. Biochem Pharmacol 72:729–738

Banks AT, Zimmerman HJ, Ishak KG, Harter JG (1995) Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology 22(3):820–827

Bankey PE, Hill S, Geldon D (1994) Sequential insult enhances liver macrophage-signaled hepatocyte dysfunction. J Surg Res 57:185–191

Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T (2001) Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410:120–124

Bao J, Shi Y, Sun H, Yin X, Yang R, Li L, Chen X, Bu H (2011) Construction of a portal implantable functional tissue-engineered liver using perfusion-decellularized matrix and hepatocytes in rats. Cell Transpl 20:753–766

Barbetta A, Massimi M, di Rosario B, Nardecchia S, de Colli M, Devirgiliis LC, Dentini M (2008) Emulsion templated scaffolds that include gelatin and glycosaminoglycans. Biomacromolecules 9:2844–2856

Barbier O, Torra IP, Sirvent A, Claudel T, Blanquart C, Duran-Sandoval D, Kuipers F, Kosykh V, Fruchart JC, Staels B (2003) FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity. Gastroenterology 124:1926–1940

Barcelo S, Mace K, Pfeifer AM, Chipman JK (1998) Production of DNA strand breaks by N-nitrosodimethylamine and 2-amino-3-methylimidazo[4,5-f]quinoline in THLE cells expressing human CYP isoenzymes and inhibition by sulforaphane. Mutat Res 402:111–120

Baribault H, Marceau N (1986) Dexamethasone and dimethylsulfoxide as distinct regulators of growth and differentiation of cultured suckling rat hepatocytes. J Cell Physiol 129:77–84

Barker N, Clevers H (2000) Catenins, Wnt signaling and cancer. Bioessays 22:961–965

Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

Bartel DP, Chen CZ (2004) Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet 5:396–400

Bartel T, Holzhütter HG (1990) Mathematical modelling of the purine metabolism of the rat liver. Biochim Biophys Acta 1035:331–339

Barter ZE, Bayliss MK, Beaune PH, Boobis AR, Carlile DJ, Edwards RJ, Houston JB, Lake BG, Lipscomb JC, Pelkonen OR, Tucker GT, Rostami-Hodjegan A (2007) Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver. Curr Drug Metab 8:33–45

Bartles JR, Feracci HM, Stieger B, Hubbard AL (1987) Biogenesis of the rat hepatocyte plasma membrane in vivo: comparison of the pathways taken by apical and basolateral proteins using subcellular fractionation. J Cell Biol 105:1241–1251

Basma H, Soto-Gutierrez A, Yannam GR, Liu L, Ito R, Yamamoto T, Ellis E, Carson SD, Sato S, Chen Y, Muirhead D, Navarro-Alvarez N, Wong RJ, Roy-Chowdhury J, Platt JL, Mercer DF, Miller JD, Strom SC, Kobayashi N, Fox IJ (2009) Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology 136:990–999

Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209–218

Batty N, Malouf GG, Issa JP (2009) Histone deacetylase inhibitors as anti-neoplastic agents. Cancer Lett 280:192–200

Bauer D, Wolfram N, Kahl GF, Hirsch-Ernst KI (2004) Transcriptional regulation of CYP2B1 induction in primary rat hepatocyte cultures: repression by epidermal growth factor is mediated via a distal enhancer region. Mol Pharmacol 65:172–180

Bauman JW, Goldsworthy TL, Dunn CS, Fox TR (1995) Inhibitory effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on rat hepatocyte proliferation induced by 2/3 partial hepatectomy. Cell Prolif 28:437–451

Bautista AP, Spolarics Z, Jaeschke H, Smith CW, Spitzer JJ (1994) Antineutrophil monoclonal antibody (1F12) alters superoxide anion release by neutrophils and Kupffer cells. J Leukoc Biol 55:328–335

Baverel G, Renault S, Faiz H, el Hage M, Gauthier C, Duplany A, Ferrier B, Martin G (2011) Protocols and applications of cellular metabolomics in safety studies using precision-cut tissue slices and carbon 13 NMR. Humana Press, Totowa

Baxter MA, Rowe C, Alder J, Harrison S, Hanley KP, Park BK, Kitteringham NR, Goldring CE, Hanley NA (2010) Generating hepatic cell lineages from pluripotent stem cells for drug toxicity screening. Stem Cell Res 5:4–22

Beard DA, Qian H (2005) Thermodynamic-based computational profiling of cellular regulatory control in hepatocyte metabolism. Am J Physiol Endocrinol Metab 288:E633–E644

Beck NB, Sidhu JS, Omiecinski CJ (2000) Baculovirus vectors repress phenobarbital-mediated gene induction and stimulate cytokine expression in primary cultures of rat hepatocytes. Gene Ther 7:1274–1283

Becker S, Reinehr R, Graf D, Vom DAHLS, Häussinger D (2007) Hydrophobic bile salts induce hepatocyte shrinkage via NADPH oxidase activation. Cell Physiol Biochem 19(1–4):89–98

Beekman JM, Boess F, Hildebrand H, Kalkuhl A, Suter L (2006) Gene expression analysis of the hepatotoxicant methapyrilene in primary rat hepatocytes: an interlaboratory study. Environ Health Perspect 114:92–99

Beerheide W, von Mach MA, Ringel M, Fleckenstein C, Schumann S, Renzing N, Hildebrandt A, Brenner W, Jensen O, Gebhard S, Reifenberg K, Bender J, Oesch F, Hengstler JG (2002) Downregulation of beta2-microglobulin in human cord blood somatic stem cells after transplantation into livers of SCID-mice: an escape mechanism of stem cells? Biochem Biophys Res Commun 294:1052–1063

Begue JM, Guguen-Guillouzo C, Pasdeloup N, Guillouzo A (1984) Prolonged maintenance of active cytochrome P-450 in adult rat hepatocytes co-cultured with another liver cell type. Hepatology 4:839–842

Behre J, Wilhelm T, von Kamp A, Ruppin E, Schuster S (2008) Structural robustness of metabolic networks with respect to multiple knockouts. J Theor Biol 252:433–441

Beigel J, Fella K, Kramer PJ, Kroeger M, Hewitt P (2008) Genomics and proteomics analysis of cultured primary rat hepatocytes. Toxicol In Vitro 22:171–181

Belzer FO, Kalayoglu M, D’Alessandro AM, Pirsch JD, Sollinger HW, Hoffmann R, Boudjema K, Southard JH (1990) Organ preservation: experience with University of Wisconsin solution and plans for the future. Clin Transpl 4:73–77

Benhamouche S, Decaens T, Godard C, Chambrey R, Rickman DS, Moinard C, Vasseur-Cognet M, Kuo CJ, Kahn A, Perret C, Colnot S (2006) Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell 10:759–770

Beraza N, Ludde T, Assmus U, Roskams T, Vander borght S, Trautwein C (2007) Hepatocyte-specific IKK gamma/NEMO expression determines the degree of liver injury. Gastroenterology 132:2504–2517

Berendsen TA, Izamis ML, Xu H, Liu Q, Hertl M, Berthiaume F, Yarmush ML, Uygun K (2011) Hepatocyte viability and adenosine triphosphate content decrease linearly over time during conventional cold storage of rat liver grafts. Transpl Proc 43:1484–1488

Bergwerk AJ, Shi X, Ford AC, Kanai N, Jacquemin E, Burk RD, Bai S, Novikoff PM, Stieger B, Meier PJ, Schuster VL, Wolkoff AW (1996) Immunologic distribution of an organic anion transport protein in rat liver and kidney. Am J Physiol 271:G231–G238

Berke G (1995) The CTL’s kiss of death. Cell 81:9–12

Berry MN, Friend DS (1969) High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol 43:506–520

Berry MN, Grivell AR, Grivell MB, Phillips JW (1997) Isolated hepatocytes–past, present and future. Cell Biol Toxicol 13:223–233

Berthiaume F, Moghe PV, Toner M, Yarmush ML (1996) Effect of extracellular matrix topology on cell structure, function, and physiological responsiveness: hepatocytes cultured in a sandwich configuration. Faseb J 10:1471–484

Bessems M, t’ Hart NA, Tolba R, Doorschodt BM, Leuvenink HG, Ploeg RJ, Minor T, Vangulik TM (2006) The isolated perfused rat liver: standardization of a time-honoured model. Lab Anim 40:236–246

Bezerra JA, Balistreri WF (2000) The unique nature of the pediatric liver. Clin Liver Dis 4:xi–xv

Bhalla S, Ozalp C, Fang S, Xiang L, Kemper JK (2004) Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha. Functional implications in hepatic cholesterol and glucose metabolism. J Biol Chem 279:45139–45147

Bhandari RN, Riccalton LA, Lewis AL, Fry JR, Hammond AH, Tendler SJ, Shakesheff KM (2001) Liver tissue engineering: a role for co-culture systems in modifying hepatocyte function and viability. Tissue Eng 7:345–357

Bharadwaj M, Illing P, Theodossis A, Purcell AW, Rossjohn J, McCluskey J (2012) Drug hypersensitivity and human leukocyte antigens of the major histocompatibility complex. Annu Rev Pharmacol Toxicol 52:401–431

Bhatia SN, Balis UJ, Yarmush ML, Toner M (1999) Effect of cell-cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells. Faseb J 13:1883–900

Bhogal RH, Hodson J, Bartlett DC, Weston CJ, Curbishley SM, Haughton E, Williams KT, Reynolds GM, Newsome PN, Adams DH, Afford SC (2011) Isolation of primary human hepatocytes from normal and diseased liver tissue: a one hundred liver experience. PLoS One 6:e18222

Bi YA, Kazolias D, Duignan DB (2006) Use of cryopreserved human hepatocytes in sandwich culture to measure hepatobiliary transport. Drug Metab Dispos 34:1658–1665

Billiar TR, Curran RD, Stuehr DJ, West MA, Bentz BG, Simmons RL (1989) An L-arginine-dependent mechanism mediates Kupffer cell inhibition of hepatocyte protein synthesis in vitro. J Exp Med 169:1467–1472

Billiar TR, Curran RD, Ferrari FK, Williams DL, Simmons RL (1990) Kupffer cell:hepatocyte cocultures release nitric oxide in response to bacterial endotoxin. J Surg Res 48:349–353

Billiar TR, Lysz TW, Curran RD, Bentz BG, Machiedo GW, Simmons RL (1990) Hepatocyte modulation of Kupffer cell prostaglandin E2 production in vitro. J Leukoc Biol 47:305–311

Billiar TR, Curran RD, Williams DL, Kispert PH (1992) Liver nonparenchymal cells are stimulated to provide interleukin 6 for induction of the hepatic acute-phase response in endotoxemia but not in remote localized inflammation. Arch Surg 127:31–36; discussion 36–37

Bissell DM, Arenson DM, Maher JJ, Roll FJ (1987) Support of cultured hepatocytes by a laminin-rich gel. Evidence for a functionally significant subendothelial matrix in normal rat liver. J Clin Invest 79:801–812

Björnsson E (2008) Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand 118:281–290

Björnsson E, Olsson R (2005) Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 42:481–489

Björnsson E, Jacobsen EI, Kalaitzakis E (2012) Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 56(2):374–380

Black MB, Budinsky RA, Dombkowski A, Cukovic D, Lecluyse EL, Ferguson SS, Thomas RS, Rowlands JC (2012) Cross-species comparisons of transcriptomic alterations in human and rat primary hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 127:199–215

Blanchard N, Alexandre E, Abadie C, Lave T, Heyd B, Mantion G, Jaeck D, Richert L, Coassolo P (2005) Comparison of clearance predictions using primary cultures and suspensions of human hepatocytes. Xenobiotica 35:1–15

Blanchard N, Hewitt NJ, Silber P, Jones H, Coassolo P, Lave T (2006) Prediction of hepatic clearance using cryopreserved human hepatocytes: a comparison of serum and serum-free incubations. J Pharm Pharmacol 58:633–641

Blanchard N, Richert L, Notter B, Delobel F, David P, Coassolo P, Lave T (2004) Impact of serum on clearance predictions obtained from suspensions and primary cultures of rat hepatocytes. Eur J Pharm Sci 23:189–199

Bleibel W, Kim S, D’Silva K, Lemmer ER (2007) Drug-induced liver injury: review article. Dig Dis Sci 52:2463–2471

Block GD, Locker J, Bowen WC, Petersen BE, Katyal S, Strom SC, Riley T, Howard TA, Michalopoulos GK (1996) Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium. J Cell Biol 132:1133–1149

Block M, Scholl E, Drasdo D (2007) Classifying the expansion kinetics and critical surface dynamics of growing cell populations. Phys Rev Lett 99:248101

Bode JG (2011) Inflammation and liver regeneration. In: Häussinger D (ed) Liver regneration. DeGruyter Verlag, Berlin

Bode JG, Albrecht U, Häussinger D, Heinrich PC, Schaper F (2011) Hepatic acute phase proteins–regulation by IL-6- and IL-1-type cytokines involving STAT3 and its crosstalk with NF-kappaB-dependent signaling. Eur J Cell Biol 91:496–505

Bode JG, Heinrich PC (2001) Interleukin-6 signaling during the acute-phase response of the liver. In: Arias IM, Boyer JL, Chisari FV, Fausto N, Schachter D, Shafritz DA (eds) The liver: biology and pathobiology, 4th edn. Lippincott Williams Wilkins, Philadelphia, pp 565–580

Boelsterli UA (2003) Idiosyncratic drug hepatotoxicity revisited: new insights from mechanistic toxicology. Toxicol Mech Methods 13:3–20

Boess F, Kamber M, Romer S, Gasser R, Muller D, Albertini S, Suter L (2003) Gene expression in two hepatic cell lines, cultured primary hepatocytes, and liver slices compared to the in vivo liver gene expression in rats: possible implications for toxicogenomics use of in vitro systems. Toxicol Sci 73:386–402

Boffetta P, Mundt KA, Adami HO, Cole P, Mandel JS (2011) TCDD and cancer: a critical review of epidemiologic studies. Crit Rev Toxicol 41:622–636

Bohme M, Muller M, Leier I, Jedlitschky G, Keppler D (1994) Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver. Gastroenterology 107:255–265

Boini KM, Graf D, Hennige AM, Koka S, Kempe DS, Wang K, Ackermann TF, Foller M, Vallon V, Pfeifer K, Schleicher E, Ullrich S, Haring HU, Häussinger D, Lang F (2009) Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1. Am J Physiol Regul Integr Comp Physiol 296:R1695–R1701

Boini KM, Graf D, Kuhl D, Häussinger D, Lang F (2009) SGK1 dependence of insulin induced hypokalemia. Pflugers Arch 457:955–961

Bojar H, Basler M, Fuchs F, Dreyfurst R, Staib W, Broelsch C (1976) Preparation of parenchymal and non-parenchymal cells from adult human liver–morphological and biochemical characteristics. J Clin Chem Clin Biochem 14:527–532

Bokhari M, Carnachan RJ, Cameron NR, Przyborski SA (2007) Novel cell culture device enabling three-dimensional cell growth and improved cell function. Biochem Biophys Res Commun 354:1095–1100

Bokhari M, Carnachan RJ, Cameron NR, Przyborski SA (2007) Culture of HepG2 liver cells on three dimensional polystyrene scaffolds enhances cell structure and function during toxicological challenge. J Anat 211:567–576

Bolleyn J, Fraczek J, Vinken M, Lizarraga D, Gaj S, van Delft JH, Rogiers V, Vanhaecke T (2011) Effect of Trichostatin A on miRNA expression in cultures of primary rat hepatocytes. Toxicol In Vitro 25:1173–1182

Bonasio R, Tu S, Reinberg D (2010) Molecular signals of epigenetic states. Science 330:612–616

Borgius LJ, Steffensen KR, Gustafsson JA, Treuter E (2002) Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP. J Biol Chem 277:49761–49766

Borlak J, Klutcka T (2004) Expression of basolateral and canalicular transporters in rat liver and cultures of primary hepatocytes. Xenobiotica 34:935–947

Borner C (2003) The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol 39:615–647

Borst P, de Wolf C, van de Wetering K (2007) Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch 453:661–673

Bort R, Mace K, Boobis A, Gomez-Lechon MJ, Pfeifer A, Castell J (1999) Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem Pharmacol 58:787–796

Bosserhoff A, Hellerbrand C (2011) Obesity and fatty liver are ‘grease’ for the machinery of hepatic fibrosis. Dig Dis 29:377–83

Botham KM, Fresnedo O, Romero JR, Ochoa B (1998) Zonal distribution of chylomicron remnant uptake in rat liver parenchymal cells. Gen Physiol Biophys 17:79–94

Bourdi M, Masubuchi Y, Reilly TP, Amouzadeh HR, Martin JL, George JW, Shah AG, Pohl LR (2002) Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology 35:289–298

Bouwens L, Baekeland M, de Zanger R, Wisse E (1986) Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology 6:718–722

Boyce FM, Bucher NL (1996) Baculovirus-mediated gene transfer into mammalian cells. Proc Natl Acad Sci USA 93:2348–2352

Boyer JL, Graf J, Meier PJ (1992) Hepatic transport systems regulating pHi, cell volume, and bile secretion. Annu Rev Physiol 54:415–438

Braakman I, Groothuis GM, Meijer DK (1987) Acinar redistribution and heterogeneity in transport of the organic cation rhodamine B in rat liver. Hepatology 7(5):849–855

Braeuning A (2009) Regulation of cytochrome P450 expression by Ras- and beta-catenin-dependent signaling. Curr Drug Metab 10:138–158

Braeuning A (2012) Interplay of β-catenin with xenobiotic-sensing receptors and its role in glutathione S-transferase expression. Curr Drug Metab 13(2):203–214

Braeuning A, Buchmann A (2009) The glycogen synthase kinase inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) is a partial agonist of the aryl hydrocarbon receptor. Drug Metab Dispos 37:1576–1580

Braeuning A, Schwarz M (2010) Zonation of heme synthesis enzymes in mouse liver and their regulation by beta-catenin and Ha-ras. Biol Chem 391:1305–1313

Braeuning A, Schwarz M (2010) Beta-Catenin as a multilayer modulator of zonal cytochrome P450 expression in mouse liver. Biol Chem 391:139–148

Braeuning A, Ittrich C, Kohle C, Hailfinger S, Bonin M, Buchmann A, Schwarz M (2006) Differential gene expression in periportal and perivenous mouse hepatocytes. Febs J 273:5051–5061

Braeuning A, Ittrich C, Kohle C, Buchmann A, Schwarz M (2007) Zonal gene expression in mouse liver resembles expression patterns of Ha-ras and beta-catenin mutated hepatomas. Drug Metab Dispos 35:503–507

Braeuning A, Menzel M, Kleinschnitz EM, Harada N, Tamai Y, Kohle C, Buchmann A, Schwarz M (2007) Serum components and activated Ha-ras antagonize expression of perivenous marker genes stimulated by beta-catenin signaling in mouse hepatocytes. Febs J 274:4766–4777

Braeuning A, Sanna R, Huelsken J, Schwarz M (2009) Inducibility of drug-metabolizing enzymes by xenobiotics in mice with liver-specific knockout of Ctnnb1. Drug Metab Dispos 37:1138–1145

Braeuning A, Singh Y, Rignall B, Buchmann A, Hammad S, Othman A, von Recklinghausen I, Godoy P, Hoehme S, Drasdo D, Hengstler JG, Schwarz M (2010) Phenotype and growth behavior of residual beta-catenin-positive hepatocytes in livers of beta-catenin-deficient mice. Histochem Cell Biol 134:469–481

Braeuning A, Kohle C, Buchmann A, Schwarz M (2011) Coordinate regulation of cytochrome P450 1a1 expression in mouse liver by the aryl hydrocarbon receptor and the beta-catenin pathway. Toxicol Sci 122:16–25

Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137:354–366

Braiterman LT, Hubbard AL (2009) Hepatocyte surface polarity: its dynamic maintenance and establishment. In: The liver. Wiley, New York, pp 73–105

Braspenning J, Holder S, Kuepper H (2010) Propagation of primary cells and use thereof. Patent EP2185690, 05–19

Braumann UD, Kuska JP (2006) A new equation for nonlinear image registration with control over the vortex structure in the displacement field. In: Proceedings of the IEEE international conference on image processing. IEEE Signal Processing Society, pp 329–332

Brendel K, Fisher RL, Krumdieck CL, Gandolfi AJ (1990) Precision-cut rat liver slices in dynamic organ culture for structure-toxicity studies. J Am Coll Toxicol 9:621

Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J (2002) The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity. Mol Endocrinol 16:2065–2076

Briz O, Serrano MA, Macias RI, Gonzalez-Gallego J, Marin JJ (2003) Role of organic anion-transporting polypeptides, OATP-A, OATP-C and OATP-8, in the human placenta-maternal liver tandem excretory pathway for foetal bilirubin. Biochem J 371:897–905

Bronger H, Konig J, Kopplow K, Steiner HH, Ahmadi R, Herold-Mende C, Keppler D, Nies AT (2005) ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Res 65:11419–11428

Brophy CM, Luebke-Wheeler JL, Amiot BP, Khan H, Remmel RP, Rinaldo P, Nyberg SL (2009) Rat hepatocyte spheroids formed by rocked technique maintain differentiated hepatocyte gene expression and function. Hepatology 49:578–586

Broughan TA, Naukam R, Tan C, van de Wiele CJ, Refai H, Teague TK (2008) Effects of hepatic zonal oxygen levels on hepatocyte stress responses. J Surg Res 145:150–160

Brown HS, Griffin M, Houston JB (2007) Evaluation of cryopreserved human hepatocytes as an alternative in vitro system to microsomes for the prediction of metabolic clearance. Drug Metab Dispos 35:293–301

Brown HS, Ito K, Galetin A, Houston JB (2005) Prediction of in vivo drug-drug interactions from in vitro data: impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant. Br J Clin Pharmacol 60:508–518

Brown ME, Rondon E, Rajesh D, Mack A, Lewis R, Feng X, Zitur LJ, Learish RD, Nuwaysir EF (2010) Derivation of induced pluripotent stem cells from human peripheral blood T lymphocytes. PLoS One 5:e11373

Brun P, Castagliuolo I, Pinzani M, Palu G, Martines D (2005) Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 289:G571–G578

Brunham LR, Kruit JK, Pape TD, Parks JS, Kuipers F, Hayden MR (2006) Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels. Circ Res 99:672–674

Brunnberg S, Andersson P, Lindstam M, Paulson I, Poellinger L, Hanberg A (2006) The constitutively active Ah receptor (CA-Ahr) mouse as a potential model for dioxin exposure–effects in vital organs. Toxicology 224:191–201

Bücher T, Sies H (1976) Mitochondrial and cytosolic redox states in perfused rat liver: methods and problems in metabolic compartmentation. In: Tager jm WJ, Söling D (eds) Use of isolated liver cells and kidney tubules in metabolic studies. North Holland Publishing Company/American Elsevier, New York/Amsterdam

Buchmann A, Schwarz M, Schmitt R, Wolf CR, Oesch F, Kunz W (1987) Development of cytochrome P-450-altered preneoplastic and neoplastic lesions during nitrosamine-induced hepatocarcinogenesis in the rat. Cancer Res 47:2911–2918

Buchmann A, Stinchcombe S, Korner W, Hagenmaier H, Bock KW (1994) Effects of 2,3,7,8-tetrachloro- and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin on the proliferation of preneoplastic liver cells in the rat. Carcinogenesis 15:1143–1150

Buchweitz JP, Ganey PE, Bursian SJ, Roth RA (2002) Underlying endotoxemia augments toxic responses to chlorpromazine: is there a relationship to drug idiosyncrasy? J Pharmacol Exp Ther 300:460–467

Budinsky RA, Lecluyse EL, Ferguson SS, Rowlands JC, Simon T (2010) Human and rat primary hepatocyte CYP1A1 and 1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and 2,3,4,7,8-pentachlorodibenzofuran. Toxicol Sci 118:224–235

Budinsky RA, Paustenbach D, Fontaine D, Landenberger B, Starr TB (2006) Recommended relative potency factors for 2,3,4,7,8-pentachlorodibenzofuran: the impact of different dose metrics. Toxicol Sci 91:275–285

Budinsky RA, Schrenk D, Simon T, Van den Berg M, Maier A, Silkworth JB, Aylward L, Brix A, Gasiewicz T, Kaminski N, Perdew G, Starr TB, Walker NJ, Rowlands JC (2012) Mode of action and dose-response framework analysis for receptor-mediated toxicity: the aryl hydrocarbon receptor as a case study. Crit Rev Toxicol (in press)

Buffler PA, Ginevan ME, Mandel JS, Watkins DK (2011) The Air Force health study: an epidemiologic retrospective. Ann Epidemiol 21:673–687

Bulera SJ, Haas MJ, Sattler CA, Li Y, Pitot HC (1997) Cell lines with heterogeneous phenotypes result from a single isolation of albumin-sv40 T-antigen transgenic rat hepatocytes. Hepatology 25:1192–1203

Burckhardt G, Burckhardt BC (2011) In vitro and in vivo evidence of the importance of organic anion transporters (OATs) in drug therapy. Springer, Berlin

Burczynski FJ, Wang GQ, Elmadhoun B, She YM, Roberts MS, Standing KG (2001) Hepatocyte [3H]-palmitate uptake: effect of albumin surface charge modification. Can J Physiol Pharmacol 79:868–875

Burger HJ, Gebhardt R, Mayer C, Mecke D (1989) Different capacities for amino acid transport in periportal and perivenous hepatocytes isolated by digitonin/collagenase perfusion. Hepatology 9:22–28

Burk O, Arnold KA, Geick A, Tegude H, Eichelbaum M (2005) A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. Biol Chem 386:503–513

Burkard A, Dahn C, Heinz S, Zutavern A, Sonntag-Buck V, Maltman D, Przyborski S, Hewitt NJ, Braspenning J (2012) Generation of proliferating human hepatocytes using upcyte((R)) technology: characterisation and applications in induction and cytotoxicity assays. Xenobiotica

Burke AS, Macmillan-Crow LA, Hinson JA (2010) Reactive nitrogen species in acetaminophen-induced mitochondrial damage and toxicity in mouse hepatocytes. Chem Res Toxicol 23:1286–1292

Burke ZD, Tosh D (2006) The Wnt/beta-catenin pathway: master regulator of liver zonation? Bioessays 28:1072–1077

Burns KA, Vanden Heuvel JP (2007) Modulation of PPAR activity via phosphorylation. Biochim Biophys Acta 1771:952–60

Bursch W, Chabicovsky M, Wastl U, Grasl-Kraupp B, Bukowska K, Taper H, Schulte-Hermann R (2005) Apoptosis in stages of mouse hepatocarcinogenesis: failure to counterbalance cell proliferation and to account for strain differences in tumor susceptibility. Toxicol Sci 85:515–529

Cai J, Zhao Y, Liu Y, Ye F, Song Z, Qin H, Meng S, Chen Y, Zhou R, Song X, Guo Y, Ding M, Deng H (2007) Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 45:1229–1239

Cailhier JF, Partolina M, Vuthoori S, Wu S, Ko K, Watson S, Savill J, Hughes J, Lang RA (2005) Conditional macrophage ablation demonstrates that resident macrophages initiate acute peritoneal inflammation. J Immunol 174:2336–2342

Caja L, Ortiz C, Bertran E, Murillo MM, Miro-Obradors MJ, Palacios E, Fabregat I (2007) Differential intracellular signalling induced by TGF-beta in rat adult hepatocytes and hepatoma cells: implications in liver carcinogenesis. Cell Signal 19:683–694

Calkin AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol 13:213–224

Calmus Y, Guechot J, Podevin P, Bonnefis MT, Giboudeau J, Poupon R (1992) Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-alpha production by monocytes. Hepatology 16:719–723

Campbell MJ, Adorini L (2006) The vitamin D receptor as a therapeutic target. Expert Opin Ther Targets 10:735–748

Campion SN, Johnson R, Aleksunes LM, Goedken MJ, van Rooijen N, Scheffer GL, Cherrington NJ, Manautou JE (2008) Hepatic Mrp4 induction following acetaminophen exposure is dependent on Kupffer cell function. Am J Physiol Gastrointest Liver Physiol 295:G294–G304

Canaple L, Nurdin N, Angelova N, Saugy D, Hunkeler D, Desvergne B (2001) Maintenance of primary murine hepatocyte functions in multicomponent polymer capsules–in vitro cryopreservation studies. J Hepatol 34:11–18

Cancado EL, Leitao RM, Carrilho FJ, Laudanna AA (1998) Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase. Am J Gastroenterol 93:1510–1517

Cantore M, Reinehr R, Sommerfeld A, Becker M, Häussinger D (2011) The Src family kinase Fyn mediates hyperosmolarity-induced Mrp2 and Bsep retrieval from canalicular membrane. J Biol Chem 286:45014–45029

Cardier JE, Schulte T, Kammer H, Kwak J, Cardier M (1999) Fas (CD95, APO-1) antigen expression and function in murine liver endothelial cells: implications for the regulation of apoptosis in liver endothelial cells. Faseb J 13:1950–1960

Carey MA, van Pelt FN (2005) Immunochemical detection of flucloxacillin adduct formation in livers of treated rats. Toxicology 216:41–48

Carlson EA, McCulloch C, Koganti A, Goodwin SB, Sutter TR, Silkworth JB (2009) Divergent transcriptomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepatocytes. Toxicol Sci 112:257–272

Carmo H, Hengstler JG, de Boer D, Ringel M, Remiao F, Carvalho F, Fernandes E, dos Reys LA, Oesch F, de Lourdes Bastos M (2005) Metabolic pathways of 4-bromo-2,5-dimethoxyphenethylamine (2C-B): analysis of phase I metabolism with hepatocytes of six species including human. Toxicology 206:75–89

Carnachan RJ, Bokhari M, Przyborski SA, Cameron NR (2006) Tailoring the morphology of emulsion-templated porous polymers. Soft Matter 2:608–616

Carr DF, Alfirevic A, Tugwood JD, Barratt BJ, Sherwood J, Smith J, Pirmohamed M, Park BK (2007) Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity. Pharmacogenet Genomics 17(11):961–972

Carraro A, Hsu WM, Kulig KM, Cheung WS, Miller ML, Weinberg EJ, Swart EF, Kaazempur-Mofrad M, Borenstein JT, Vacanti JP, Neville C (2008) In vitro analysis of a hepatic device with intrinsic microvascular-based channels. Biomed Microdevices 10:795–805

Cascorbi I (2011) P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations. Handb Exp Pharmacol 201:261–283

Cassio D, Hamon-Benais C, Guerin M, Lecoq O (1991) Hybrid cell lines constitute a potential reservoir of polarized cells: isolation and study of highly differentiated hepatoma-derived hybrid cells able to form functional bile canaliculi in vitro. J Cell Biol 115:1397–1408

Casteleijn E, Kuiper J, van Rooij HC, Kamps JA, Koster JF, van Berkel TJ (1988) Endotoxin stimulates glycogenolysis in the liver by means of intercellular communication. J Biol Chem 263:6953–6955

Castell JV, Hernandez D, Gomez-Foix AM, Guillen I, Donato T, Gomez-Lechon MJ (1997) Adenovirus-mediated gene transfer into human hepatocytes: analysis of the biochemical functionality of transduced cells. Gene Ther 4:455–464

Castell JV, Jover R, Martinez-Jimenez CP, Gomez-Lechon MJ (2006) Hepatocyte cell lines: their use, scope and limitations in drug metabolism studies. Expert Opin Drug Metab Toxicol 2:183–212

Castilho-Fernandes A, de Almeida DC, Fontes AM, Melo FU, Picanço-Castro V, Freitas MC, Orellana MD, Palma PV, Hackett PB, Friedman SL, Covas DT (2011) Human hepatic stellate cell line (LX-2) exhibits characteristics of bone marrow-derived mesenchymal stem cells. Exp Mol Pathol 91:664–672

Cattley RC, Deluca J, Elcombe C, Fenner-Crisp P, Lake BG, Marsman DS, Pastoor TA, Popp JA, Robinson DE, Schwetz B, Tugwood J, Wahli W (1998) Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol 27:47–60

Cattori V, Eckhardt U, Hagenbuch B (1999) Molecular cloning and functional characterization of two alternatively spliced Ntcp isoforms from mouse liver1. Biochim Biophys Acta 1445:154–159

Cattori V, van Montfoort JE, Stieger B, Landmann L, Meijer DK, Winterhalter KH, Meier PJ, Hagenbuch B (2001) Localization of organic anion transporting polypeptide 4 (Oatp4) in rat liver and comparison of its substrate specificity with Oatp1, Oatp2 and Oatp3. Pflugers Arch 443:188–195

Ceppi P, Mudduluru G, Kumarswamy R, Rapa I, Scagliotti GV, Papotti M, Allgayer H (2010) Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol Cancer Res 8:1207–1216

Cha HJ, Ko MJ, Ahn SM, Ahn JI, Shin HJ, Jeong HS, Kim HS, Choi SO, Kim EJ (2010) Identification of classifier genes for hepatotoxicity prediction in non steroidal anti inflammatory drugs. Mol Cell Toxicol 6:247–253

Chai J, Luo D, Wu X, Wang H, He Y, Li Q, Zhang Y, Chen L, Peng ZH, Xiao T, Wang R, Chen W (2011) Changes of organic anion transporter MRP4 and related nuclear receptors in human obstructive cholestasis. J Gastrointest Surg 15:996–1004

Chalasani N, Bjornsson E (2010) Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology 138:2246–2259

Chalhoub E, Hanson RW, Belovich JM (2007) A computer model of gluconeogenesis and lipid metabolism in the perfused liver. Am J Physiol Endocrinol Metab 293:E1676–E1686

Chalhoub E, Xie L, Balasubramanian V, Kim J, Belovich J (2007) A distributed model of carbohydrate transport and metabolism in the liver during rest and high-intensity exercise. Ann Biomed Eng 35:474–491

Chan C, Berthiaume F, Nath BD, Tilles AW, Toner M, Yarmush ML (2004) Hepatic tissue engineering for adjunct and temporary liver support: critical technologies. Liver Transpl 10:1331–1342

Chan C, Berthiaume F, Washizu J, Toner M, Yarmush ML (2002) Metabolic pre-conditioning of cultured cells in physiological levels of insulin: generating resistance to the lipid-accumulating effects of plasma in hepatocytes. Biotechnol Bioeng 78:753–760

Chang LJ, Gay EE (2001) The molecular genetics of lentiviral vectors–current and future perspectives. Curr Gene Ther 1:237–251

Chang DW, Xing Z, Capacio VL, Peter ME, Yang X (2003) Interdimer processing mechanism of procaspase-8 activation. Embo J 22:4132–4142

Chang J, Nicolas E, Marks D, Sander C, Lerro A, Buendia MA, Xu C, Mason WS, Moloshok T, Bort R, Zaret KS, Taylor JM (2004) miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol 1:106–113

Chang H, Wang YJ, Chang LW, Lin P (2005) A histochemical and pathological study on the interrelationship between TCDD-induced AhR expression, AhR activation, and hepatotoxicity in mice. J Toxicol Environ Health A 68:1567–1579

Chang Y, Moody DE, McCance-Katz EF (2006) Novel metabolites of buprenorphine detected in human liver microsomes and human urine. Drug Metab Dispos 34:440–448

Chang L, Kamata H, Solinas G, Luo JL, Maeda S, Venuprasad K, Liu YC, Karin M (2006) The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 124:601–613

Chang TT, Hughes-Fulford M (2009) Monolayer and spheroid culture of human liver hepatocellular carcinoma cell line cells demonstrate distinct global gene expression patterns and functional phenotypes. Tissue Eng Part A 15:559–567

Chen D, Park Y, Kemper B (1994) Differential protein binding and transcriptional activities of HNF-4 elements in three closely related CYP2C genes. DNA Cell Biol 13:771–779

Chen W, Chiang JY (2003) Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4alpha (HNF4alpha). Gene 313:71–82

Chen Q, Kon J, Ooe H, Sasaki K, Mitaka T (2007) Selective proliferation of rat hepatocyte progenitor cells in serum-free culture. Nat Protoc 2:1197–1205

Chen C, Stock JL, Liu X, Shi J, van Deusen JW, Dimattia DA, Dullea RG, de Morais SM (2008) Utility of a novel Oatp1b2 knockout mouse model for evaluating the role of Oatp1b2 in the hepatic uptake of model compounds. Drug Metab Dispos 36:1840–1845

Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10:826–837

Chen AA, Thomas DK, Ong LL, Schwartz RE, Golub TR, Bhatia SN (2011) Humanized mice with ectopic artificial liver tissues. Proc Natl Acad Sci USA 108:11842–11847

Chen YF, Tseng CY, Wang HW, Kuo HC, Yang VW, Lee OK (2012) Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol. Hepatology 55(4):1193–1203

Cheng SH, Rich DP, Marshall J, Gregory RJ, Welsh MJ, Smith AE (1991) Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel. Cell 66:1027–1036

Cheng X, Blumenthal RM (2008) Mammalian DNA methyltransferases: a structural perspective. Structure 16:341–350

Cheng J, Zhou L, Xie QF, Xie HY, Wei XY, Gao F, Xing CY, Xu X, Li LJ, Zheng SS (2010) The impact of miR-34a on protein output in hepatocellular carcinoma HepG2 cells. Proteomics 10:1557–1572

Cheng F, Theodorescu D, Schulman IG, Lee JK (2011) In vitro transcriptomic prediction of hepatotoxicity for early drug discovery. J Theor Biol 290:27–36

Chesire DR, Dunn TA, Ewing CM, Luo J, Isaacs WB (2004) Identification of aryl hydrocarbon receptor as a putative Wnt/beta-catenin pathway target gene in prostate cancer cells. Cancer Res 64:2523–2533

Chessman D, Kostenko L, Lethborg T, Purcell AW, Williamson NA, Chen Z, Kjer-Nielsen L, Mifsud NA, Tait BD, Holdsworth R, Almeida CA, Nolan D, Macdonald WA, Archbold JK, Kellerher AD, Marriott D, Mallal S, Bharadwaj M, Rossjohn J, McCluskey J (2008) Human leukocyte antigen class I-restricted activation of CD8 + T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 28:822–832

Chia SM, Lin PC, Yu H (2005) TGF-beta1 regulation in hepatocyte-NIH3T3 co-culture is important for the enhanced hepatocyte function in 3D microenvironment. Biotechnol Bioeng 89:565–573

Chiang JY, Kimmel R, Weinberger C, Stroup D (2000) Farnesoid X receptor responds to bile acids and represses cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription. J Biol Chem 275:10918–10924

Chiang JY, Kimmel R, Stroup D (2001) Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene 262:257–65

Chiang JY (2003) Bile acid regulation of hepatic physiology: III. Bile acids and nuclear receptors. Am J Physiol Gastrointest Liver Physiol 284:G349–G356

Chiang JY (2009) Hepatocyte nuclear factor 4alpha regulation of bile acid and drug metabolism. Expert Opin Drug Metab Toxicol 5:137–147

Chin KV, Kong AN (2002) Application of DNA microarrays in pharmacogenomics and toxicogenomics. Pharm Res 19:1773–1778

Cho CH, Berthiaume F, Tilles AW, Yarmush ML (2008) A new technique for primary hepatocyte expansion in vitro. Biotechnol Bioeng 101:345–356

Cho CH, Park J, Nagrath D, Tilles AW, Berthiaume F, Toner M, Yarmush ML (2007) Oxygen uptake rates and liver-specific functions of hepatocyte and 3T3 fibroblast co-cultures. Biotechnol Bioeng 97:188–199

Cho CH, Park J, Tilles AW, Berthiaume F, Toner M, Yarmush ML (2010) Layered patterning of hepatocytes in co-culture systems using microfabricated stencils. Biotechniques 48:47–52

Cho CS, Goto M, Kobayashi A, Kobayashi K, Akaike T (1996) Effect of ligand orientation on hepatocyte attachment onto the poly(N-p-vinylbenzyl-o-beta-D-galactopyranosyl-D-gluconamide) as a model ligand of asialoglycoprotein. J Biomater Sci Polym Ed 7:1097–1104

Cho CS, Seo SJ, Park IK, Kim SH, Kim TH, Hoshiba T, Harada I, Akaike T (2006) Galactose-carrying polymers as extracellular matrices for liver tissue engineering. Biomaterials 27:576–585

Chopra M, Schrenk D (2011) Dioxin toxicity, aryl hydrocarbon receptor signaling, and apoptosis-persistent pollutants affect programmed cell death. Crit Rev Toxicol 41:292–320

Choudhuri S (2010) Small noncoding RNAs: biogenesis, function, and emerging significance in toxicology. J Biochem Mol Toxicol 24:195–216

Chow EC, Durk MR, Cummins CL, Pang KS (2011) 1Alpha,25-dihydroxyvitamin D3 up-regulates P-glycoprotein via the vitamin D receptor and not farnesoid X receptor in both fxr(−/−) and fxr(+/+) mice and increased renal and brain efflux of digoxin in mice in vivo. J Pharmacol Exp Ther 337:846–859

Chu YS, Dufour S, Thiery JP, Perez E, Pincet F (2005) Johnson-Kendall-Roberts theory applied to living cells. Phys Rev Lett 94(2):028102

Chu XY, Kato Y, Niinuma K, Sudo KI, Hakusui H, Sugiyama Y (1997) Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J Pharmacol Exp Ther 281:304–314

Chu CC, Pan KL, Yao HT, Hsu JT (2011) Development of a whole-cell screening system for evaluation of the human CYP1A2-mediated metabolism. Biotechnol Bioeng 108:2932–2940

Chua KN, Lim WS, Zhang P, Lu H, Wen J, Ramakrishna S, Leong KW, Mao HQ (2005) Stable immobilization of rat hepatocyte spheroids on galactosylated nanofiber scaffold. Biomaterials 26:2537–2547

Chuang YH, Lian ZX, Yang GX, Shu SA, Moritoki Y, Ridgway WM, Ansari AA, Kronenberg M, Flavell RA, Gao B, Gershwin ME (2008) Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology 47:571–580

Chung JY, Cho JY, Yu KS, Kim JR, Oh DS, Jung HR, Lim KS, Moon KH, Shin SG, Jang IJ (2005) Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 78:342–350

Chung TW, Yang J, Akaike T, Cho KY, Nah JW, Kim SI, Cho CS (2002) Preparation of alginate/galactosylated chitosan scaffold for hepatocyte attachment. Biomaterials 23:2827–2834

Clayton DF, Darnell JE Jr (1983) Changes in liver-specific compared to common gene transcription during primary culture of mouse hepatocytes. Mol Cell Biol 3:1552–1561

Clayton DF, Harrelson AL, Darnell JE Jr (1985) Dependence of liver-specific transcription on tissue organization. Mol Cell Biol 5:2623–2632

Cohen SM, Storer RD, Criswell KA, Doerrer NG, Dellarco VL, Pegg DG, Wojcinski ZW, Malarkey DE, Jacobs AC, Klaunig JE, Swenberg JA, Cook JC (2009) Hemangiosarcoma in rodents: mode-of-action evaluation and human relevance. Toxicol Sci 111:4–18

Coleman R (1987) Biochemistry of bile secretion. Biochem J 244:249–261

Colletti M, Cicchini C, Conigliaro A, Santangelo L, Alonzi T, Pasquini E, Tripodi M, Amicone L (2009) Convergence of Wnt signaling on the HNF4alpha-driven transcription in controlling liver zonation. Gastroenterology 137:660–672

Colnot S, Decaens T, Niwa-Kawakita M, Godard C, Hamard G, Kahn A, Giovannini M, Perret C (2004) Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci USA 101:17216–17221

Comar JF, Suzuki-Kemmelmeier F, Constantin J, Bracht A (2010) Hepatic zonation of carbon and nitrogen fluxes derived from glutamine and ammonia transformations. J Biomed Sci 17:1

Conde de La Rosa L, Schoemaker MH, Vrenken TE, Buist-Homan M, Havinga R, Jansen PL, Moshage H (2006) Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: involvement of JNK and ERK MAP kinases. J Hepatol 44:918–929

Condreay JP, Witherspoon SM, Clay WC, Kost TA (1999) Transient and stable gene expression in mammalian cells transduced with a recombinant baculovirus vector. Proc Natl Acad Sci USA 96:127–132

Connolly EC, van Doorslaer K, Rogler LE, Rogler CE (2011) Overexpression of miR-21 promotes an in vitro metastatic phenotype by targeting the tumor suppressor RHOB. Mol Cancer Res 8:691–700

Connor KT, Aylward LL (2006) Human response to dioxin: aryl hydrocarbon receptor (AhR) molecular structure, function, and dose-response data for enzyme induction indicate an impaired human AhR. J Toxicol Environ Health B Crit Rev 9:147–171

Corazza N, Jakob S, Schaer C, Frese S, Keogh A, Stroka D, Kassahn D, Torgler R, Mueller C, Schneider P, Brunner T (2006) TRAIL receptor-mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality. J Clin Invest 116:2493–2499

Corchero J, Granvil CP, Akiyama TE, Hayhurst GP, Pimprale S, Feigenbaum L, Idle JR, Gonzalez FJ (2001) The CYP2D6 humanized mouse: effect of the human CYP2D6 transgene and HNF4alpha on the disposition of debrisoquine in the mouse. Mol Pharmacol 60:1260–1267

Corchero J, Martin-Partido G, Dallas SL, Fernandez-Salguero PM (2004) Liver portal fibrosis in dioxin receptor-null mice that overexpress the latent transforming growth factor-beta-binding protein-1. Int J Exp Pathol 85:295–302

Cosgrove BD, King BM, Hasan MA, Alexopoulos LG, Farazi PA, Hendriks BS, Griffith LG, Sorger PK, Tidor B, Xu JJ, Lauffenburger DA (2009) Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. Toxicol Appl Pharmacol 237:317–330

Coundouris JA, Grant MH, Engeset J, Petrie JC, Hawksworth GM (1993) Cryopreservation of human adult hepatocytes for use in drug metabolism and toxicity studies. Xenobiotica 23:1399–1409

Courjault-Gautier F, Antoine B, Bens M, Vallet V, Cluzeaud F, Pringault E, Kahn A, Toutain H, Vandewalle A (1997) Activity and inducibility of drug-metabolizing enzymes in immortalized hepatocyte-like cells (mhPKT) derived from a L-PK/Tag1 transgenic mouse. Exp Cell Res 234:362–372

Cover C, Mansouri A, Knight TR, Bajt ML, Lemasters JJ, Pessayre D, Jaeschke H (2005) Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity. J Pharmacol Exp Ther 315:879–887

Cover C, Liu J, Farhood A, Malle E, Waalkes MP, Bajt ML, Jaeschke H (2006) Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 216(1):98–107

Craddock AL, Love MW, Daniel RW, Kirby LC, Walters HC, Wong MH, Dawson PA (1998) Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am J Physiol 274:G157–G169

Crespi CL, Miller VP (1999) The use of heterologously expressed drug metabolizing enzymes–state of the art and prospects for the future. Pharmacol Ther 84:121–131

Crestani M, de Fabiani E, Caruso D, Mitro N, Gilardi F, Vigil Chacon AB, Patelli R, Godio C, Galli G (2004) LXR (liver X receptor) and HNF-4 (hepatocyte nuclear factor-4): key regulators in reverse cholesterol transport. Biochem Soc Trans 32:92–96

Crispe IN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27:147–163

Csanaky IL, Lu H, Zhang Y, Ogura K, Choudhuri S, Klaassen CD (2011) Organic anion-transporting polypeptide 1b2 (Oatp1b2) is important for the hepatic uptake of unconjugated bile acids: Studies in Oatp1b2-null mice. Hepatology 53:272–281

Cui Y, Konig J, Buchholz JK, Spring H, Leier I, Keppler D (1999) Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol 55:929–37

Cui Y, Konig J, Leier I, Buchholz U, Keppler D (2001) Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem 276:9626–9630

Curcio E, Salerno S, Barbieri G, de Bartolo L, Drioli E, Bader A (2007) Mass transfer and metabolic reactions in hepatocyte spheroids cultured in rotating wall gas-permeable membrane system. Biomaterials 28:5487–5497

Curran RD, Billiar TR, West MA, Bentz BG, Simmons RL (1988) Effect of interleukin 2 on Kupffer cell activation. Interleukin 2 primes and activates Kupffer cells to suppress hepatocyte protein synthesis in vitro. Arch Surg 123:1373–1378

Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB (1999) OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 27:866–871

D’Aldebert E, Biyeyeme Bi Mve MJ, Mergey M, Wendum D, Firrincieli D, Coilly A, Fouassier L, Corpechot C, Poupon R, Housset C, Chignard N (2009) Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology 136:1435–1443

D’Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK, Baetge EE (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24:1392–1401

Dahlin DC, Miwa GT, Lu AY, Nelson SD (1984) N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 81:1327–1331

Daley WP, Peters SB, Larsen M (2008) Extracellular matrix dynamics in development and regenerative medicine. J Cell Sci 121:255–264

Dalton PD, Woodfield T, Hutmacher DW (2009) Snapshot: Polymer scaffolds for tissue engineering. Biomaterials 30:701–702

Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP (2007) Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 132:272–281

Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’Er I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pirmohamed M, Aithal GP, Day CP (2009) HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 41:816–819

Dambach DM, Andrews BA, Moulin F (2005) New technologies and screening strategies for hepatotoxicity: use of in vitro models. Toxicol Pathol 33:17–26

Dan YY, Riehle KJ, Lazaro C, Teoh N, Haque J, Campbell JS, Fausto N (2006) Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc Natl Acad Sci USA 103:9912–9917

Dannenberg LO, Chen HJ, Tian H, Edenberg HJ (2006) Differential regulation of the alcohol dehydrogenase 1B (ADH1B) and ADH1C genes by DNA methylation and histone deacetylation. Alcohol Clin Exp Res 30:928–937

Dannenberg LO, Edenberg HJ (2006) Epigenetics of gene expression in human hepatoma cells: expression profiling the response to inhibition of DNA methylation and histone deacetylation. BMC Genomics 7:181

Darr TB, Hubel A (2001) Postthaw viability of precultured hepatocytes. Cryobiology 42:11–20

Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E (2009) Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis 4:1

Dawson PA, Mychaleckyj JC, Fossey SC, Mihic SJ, Craddock AL, Bowden DW (2001) Sequence and functional analysis of GLUT10: a glucose transporter in the Type 2 diabetes-linked region of chromosome 20q12-13.1. Mol Genet Metab 74:186–199

Dawson PA, Lan T, Rao A (2009) Bile acid transporters. J Lipid Res 50:2340–2357

Dawson S, Stahl S, Paul N, Barber J, Kenna JG (2012) In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans. Drug Metab Dispos 40:130–138

Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114:842–845

de Bartolo L, Salerno S, Morelli S, Giorno L, Rende M, Memoli B, Procino A, Andreucci VE, Bader A, Drioli E (2006) Long-term maintenance of human hepatocytes in oxygen-permeable membrane bioreactor. Biomaterials 27:4794–4803

de Bruyn T, Ye ZW, Peeters A, Sahi J, Baes M, Augustijns PF, Annaert PP (2011) Determination of OATP-, NTCP- and OCT-mediated substrate uptake activities in individual and pooled batches of cryopreserved human hepatocytes. Eur J Pharm Sci 43:297–307

de Graaf IA, de Kanter R, de Jager MH, Camacho R, Langenkamp E, van de Kerkhof EG, Groothuis GM (2006) Empirical validation of a rat in vitro organ slice model as a tool for in vivo clearance prediction. Drug Metab Dispos 34:591–599

de Graaf IA, Groothuis GM, Olinga P (2007) Precision-cut tissue slices as a tool to predict metabolism of novel drugs. Expert Opin Drug Metab Toxicol 3:879–898

de Graaf IA, Draaisma AL, Schoeman O, Fahy GM, Groothuis GM, Koster HJ (2007) Cryopreservation of rat precision-cut liver and kidney slices by rapid freezing and vitrification. Cryobiology 54:1–12

de Graaf IA, Olinga P, de Jager MH, Merema MT, de Kanter R, van de Kerkhof EG, Groothuis GM (2010) Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. Nat Protoc 5:1540–1551

de la Cruz CC, Kirmizis A, Simon MD, Isono K, Koseki H, Panning B (2007) The polycomb group protein SUZ12 regulates histone H3 lysine 9 methylation and HP1 alpha distribution. Chromosome Res 15:299–314

Deakin JA, Blaum BS, Gallagher JT, Uhrin D, Lyon M (2009) The binding properties of minimal oligosaccharides reveal a common heparan sulfate/dermatan sulfate-binding site in hepatocyte growth factor/scatter factor that can accommodate a wide variety of sulfation patterns. J Biol Chem 284:6311–6321

Decaens T, Godard C, de Reynies A, Rickman DS, Tronche F, Couty JP, Perret C, Colnot S (2008) Stabilization of beta-catenin affects mouse embryonic liver growth and hepatoblast fate. Hepatology 47:247–258

Del Castillo-Olivares A, Campos JA, Pandak WM, Gil G (2004) The role of alpha1-fetoprotein transcription factor/LRH-1 in bile acid biosynthesis: a known nuclear receptor activator that can act as a suppressor of bile acid biosynthesis. J Biol Chem 279:16813–16821

Delacour D, Jacob R (2006) Apical protein transport. Cell Mol Life Sci 63:2491–2505

Deleve LD (1996) Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation. Hepatology 24:830–837

Deng X, Luyendyk JP, Ganey PE, Roth RA (2009) Inflammatory stress and idiosyncratic hepatotoxicity: hints from animal models. Pharmacol Rev 61:262–282

Deng Y, Ren X, Yang L, Lin Y, Wu X (2003) A JNK-dependent pathway is required for TNFalpha-induced apoptosis. Cell 115:61–70

Denison MS, Soshilov AA, He G, Degroot DE, Zhao B (2011) Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol Sci 124:1–22

Denk W, Strickler JH, Webb WW (1990) Two-photon laser scanning fluorescence microscopy. Science 248:73–76

Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC (1999) Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol 144:891–901

Desbarats J, Newell MK (2000) Fas engagement accelerates liver regeneration after partial hepatectomy. Nat Med 6:920–923

Deshpande RR, Koch-Kirsch Y, Maas R, John GT, Krause C, Heinzle E (2005) Microplates with integrated oxygen sensors for kinetic cell respiration measurement and cytotoxicity testing in primary and secondary cell lines. Assay Drug Dev Technol 3:299–307

Devereaux BM, Crawford DH, Purcell P, Powell LW, Roeser HP (1995) Flucloxacillin associated cholestatic hepatitis. An Australian and Swedish epidemic? Eur J Clin Pharmacol 49:81–85

di Mambro AJ, Parker R, McCune A, Gordon F, Dayan CM, Collins P (2011) In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis. Hepatology 53:1316–1322

Ding BS, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, Mittal V, Kobayashi H, Shido K, Lyden D, Sato TN, Rabbany SY, Rafii S (2010) Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468:310–315

Direnzo J, Soderstrom M, Kurokawa R, Ogliastro MH, Ricote M, Ingrey S, Horlein A, Rosenfeld MG, Glass CK (1997) Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors. Mol Cell Biol 17:2166–2176

Docoslis A, Kalogerakis N, Behie LA (1999) Dielectrophoretic forces can be safely used to retain viable cells in perfusion cultures of animal cells. Cytotechnology 30:133–142

Doege H, Schurmann A, Bahrenberg G, Brauers A, Joost HG (2000) GLUT8, a novel member of the sugar transport facilitator family with glucose transport activity. J Biol Chem 275:16275–16280

Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, Mayberg MR, Bengez L, Janigro D (2001) Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 42:1501–1506

Donaldson PT, Daly AK, Henderson J, Graham J, Pirmohamed M, Bernal W, Day CP, Aithal GP (2010) Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury. J Hepatol 53(6):1049–1053

Donato MT, Hallifax D, Picazo L, Castell JV, Houston JB, Gomez-Lechon MJ, Lahoz A (2010) Metabolite formation kinetics and intrinsic clearance of phenacetin, tolbutamide, alprazolam, and midazolam in adenoviral cytochrome P450-transfected HepG2 cells and comparison with hepatocytes and in vivo. Drug Metab Dispos 38:1449–1455

Donato MT, Lahoz A, Montero S, Bonora A, Pareja E, Mir J, Castell JV, Gomez-Lechon MJ (2008) Functional assessment of the quality of human hepatocyte preparations for cell transplantation. Cell Transpl 17:1211–1219

Donato MT, Lahoz A, Castell JV, Gomez-Lechon MJ (2008) Cell lines: a tool for in vitro drug metabolism studies. Curr Drug Metab 9:1–11

Donner MG, Keppler D (2001) Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology 34:351–359

Dooley S, Streckert M, Delvoux B, Gressner AM (2001) Expression of Smads during in vitro transdifferentiation of hepatic stellate cells to myofibroblasts. Biochem Biophys Res Commun 283:554–562

Dooley S, ten Dijke P (2012) TGF-beta in progression of liver disease. Cell Tissue Res 347:245–256

Dorko K, Freeswick PD, Bartoli F, Cicalese L, Bardsley BA, Tzakis A, Nussler AK (1994) A new technique for isolating and culturing human hepatocytes from whole or split livers not used for transplantation. Cell Transplant 3:387–395

Dou M, de Sousa G, Lacarelle B, Placidi M, de La Porte PL, Domingo M, Lafont H, Rahmani R (1992) Thawed human hepatocytes in primary culture. Cryobiology 29:454–469

Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M (1997) p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha. J Biol Chem 272:33435–33443

Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M (1999) Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein. J Biol Chem 274:15901–15907

Dragan YP, Schrenk D (2000) Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion. Food Addit Contam 17:289–302

Drasdo D (2005) Coarse Graining in Simulated Cell Populations. Adv. Complex Syst 2&3:319–363

Drasdo D, Hoehme S, Block M (2007) On the role of physics in the growth and pattern formation of multi-cellular systems: what can we learn from individual-cell based models? J Stat Phys 128(59):287–345

Drasdo D, Hoehme S (2012) Modeling the impact of granular embedding media, and pulling versus pushing cells on growing cell clones. New J Phys 14:055025

Dresser GK, Kim RB, Bailey DG (2005) Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides. Clin Pharmacol Ther 77:170–177

Drewes T, Senkel S, Holewa B, Ryffel GU (1996) Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol Cell Biol 16:925–931

Drocourt L, Ourlin JC, Pascussi JM, Maurel P, Vilarem MJ (2002) Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes. J Biol Chem 277:25125–25132

Duan Y, Catana A, Meng Y, Yamamoto N, He S, Gupta S, Gambhir SS, Zern MA (2007) Differentiation and enrichment of hepatocyte-like cells from human embryonic stem cells in vitro and in vivo. Stem Cells 25:3058–3068

Duarte NC, Becker SA, Jamshidi N, Thiele I, Mo ML, Vo TD, Srivas R, Palsson BO (2007) Global reconstruction of the human metabolic network based on genomic and bibliomic data. Proc Natl Acad Sci USA 104:1777–1782

Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115:56–65

Dunn JC, Tompkins RG, Yarmush ML (1991) Long-term in vitro function of adult hepatocytes in a collagen sandwich configuration. Biotechnol Prog 7:237–245

Dunn JC, Tompkins RG, Yarmush ML (1992) Hepatocytes in collagen sandwich: evidence for transcriptional and translational regulation. J Cell Biol 116:1043–1053

Dunn JC, Yarmush ML, Koebe HG, Tompkins RG (1989) Hepatocyte function and extracellular matrix geometry: long-term culture in a sandwich configuration. Faseb J 3:174–177

Duprez L, Bertrand MJ, Vanden Berghe T, Dondelinger Y, Festjens V, Vandenabeele P (2012) Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1 kinase-dependent apoptosis. J Biol Chem 287:14863–14872

Duret C, Gerbal-Chaloin S, Ramos J, Fabre JM, Jacquet E, Navarro F, Blanc P, Sa-Cunha A, Maurel P, Daujat-Chavanieu M (2007) Isolation, characterization, and differentiation to hepatocyte-like cells of nonparenchymal epithelial cells from adult human liver. Stem Cells 25:1779–1790

Durrin LK, Mann RK, Kayne PS, Grunstein M (1991) Yeast histone H4 N-terminal sequence is required for promoter activation in vivo. Cell 65:1023–1031

Echchgadda I, Song CS, Roy AK, Chatterjee B (2004) Dehydroepiandrosterone sulfotransferase is a target for transcriptional induction by the vitamin D receptor. Mol Pharmacol 65:720–729

Eechoute K, Franke RM, Loos WJ, Scherkenbach LA, Boere I, Verweij J, Gurney H, Kim RB, Tirona RG, Mathijssen RH, Sparreboom A (2011) Environmental and genetic factors affecting transport of imatinib by OATP1A2. Clin Pharmacol Ther 89:816–820

Eichelbaum M, Ingelman-Sundberg M, Evans WE (2006) Pharmacogenomics and individualized drug therapy. Annu Rev Med 57:119–137

Einarsson K, Alvelius G, Hillebrant CG, Reihner E, Bjorkhem I (1996) Concentration of unsulfated lithocholic acid in portal and systemic venous plasma: evidence that lithocholic acid does not down regulate the hepatic cholesterol 7 alpha-hydroxylase activity in gallstone patients. Biochim Biophys Acta 1317:19–26

Eisenberg ML, Maker AV, Slezak LA, Nathan JD, Sritharan KC, Jena BP, Geibel JP, Andersen DK (2005) Insulin receptor (IR) and glucose transporter 2 (GLUT2) proteins form a complex on the rat hepatocyte membrane. Cell Physiol Biochem 15:51–58

Eissing T, Conzelmann H, Gilles ED, Allgower F, Bullinger E, Scheurich P (2004) Bistability analyses of a caspase activation model for receptor-induced apoptosis. J Biol Chem 279:36892–7

Elaut G, Henkens T, Papeleu P, Snykers S, Vinken M, Vanhaecke T, Rogiers V (2006) Molecular mechanisms underlying the dedifferentiation process of isolated hepatocytes and their cultures. Curr Drug Metab 7:629–660

Elferink CJ, Ge NL, Levine A (2001) Maximal aryl hydrocarbon receptor activity depends on an interaction with the retinoblastoma protein. Mol Pharmacol 59:664–673

Elferink MG, Olinga P, Draaisma AL, Merema MT, Bauerschmidt S, Polman J, Schoonen WG, Groothuis GM (2008) Microarray analysis in rat liver slices correctly predicts in vivo hepatotoxicity. Toxicol Appl Pharmacol 229:300–309

Elferink MG, Olinga P, Draaisma AL, Merema MT, Faber KN, Slooff MJ, Meijer DK, Groothuis GM (2004) LPS-induced downregulation of MRP2 and BSEP in human liver is due to a posttranscriptional process. Am J Physiol Gastrointest Liver Physiol 287:G1008–G1016

Elferink MG, Olinga P, van Leeuwen EM, Bauerschmidt S, Polman J, Schoonen WG, Heisterkamp SH, Groothuis GM (2011) Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol 253:57–69

Ellinger-Ziegelbauer H, Gmuender H, Bandenburg A, Ahr HJ (2008) Prediction of a carcinogenic potential of rat hepatocarcinogens using toxicogenomics analysis of short-term in vivo studies. Mutat Res 637:23–39

Ellinger-Ziegelbauer H, Stuart B, Wahle B, Bomann W, Ahr HJ (2004) Characteristic expression profiles induced by genotoxic carcinogens in rat liver. Toxicol Sci 77:19–34

Elliott JC, Dover SD (1982) X-ray microtomography. J Microsc 126:211–213

Elmen J, Lindow M, Silahtaroglu A, Bak M, Christensen M, Lind-Thomsen A, Hedtjarn M, Hansen JB, Hansen HF, Straarup EM, McCullagh K, Kearney P, Kauppinen S (2008) Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res 36:1153–1162

Elmen J, Lindow M, Schutz S, Lawrence M, Petri A, Obad S, Lindholm M, Hedtjarn M, Hansen HF, Berger U, Gullans S, Kearney P, Sarnow P, Straarup EM, Kauppinen S (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452:896–869

Eloranta JJ, Jung D, Kullak-Ublick GA (2006) The human Na + -taurocholate cotransporting polypeptide gene is activated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and suppressed by bile acids via a small heterodimer partner-dependent mechanism. Mol Endocrinol 20:65–79

Elvevold K, Smedsrod B, Martinez I (2008) The liver sinusoidal endothelial cell: a cell type of controversial and confusing identity. Am J Physiol Gastrointest Liver Physiol 294:G391–G400

Emoto C, Murase S, Iwasaki K (2006) Approach to the prediction of the contribution of major cytochrome P450 enzymes to drug metabolism in the early drug-discovery stage. Xenobiotica 36:671–683

EPA (2012) EPA’s reanalysis of key issues related to dioxin toxicity and response to NAS Comments. Environmental Protection Agency (EPA), Washington, DC

Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP (2006) miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3:87–98

Essa S, Denzer N, Mahlknecht U, Klein R, Collnot EM, Tilgen W, Reichrath J (2010) VDR microRNA expression and epigenetic silencing of vitamin D signaling in melanoma cells. J Steroid Biochem Mol Biol 121:110–113

Esser C (2012) Biology and function of the aryl hydrocarbon receptor: report of an international and interdisciplinary conference. Arch Toxicol 86:1323–1329

Esteller A (2008) Physiology of bile secretion. World J Gastroenterol 14:5641–5649

Evans WH (1980) A biochemical dissection of the functional polarity of the plasma membrane of the hepatocyte. Biochim Biophys Acta 604:27–64

Evers R, de Haas M, Sparidans R, Beijnen J, Wielinga PR, Lankelma J, Borst P (2000) Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export. Br J Cancer 83:375–383

Evseenko DA, Paxton JW, Keelan JA (2006) ABC drug transporter expression and functional activity in trophoblast-like cell lines and differentiating primary trophoblast. Am J Physiol Regul Integr Comp Physiol 290:R1357–R1365

Eyhorn S, Schlayer HJ, Henninger HP, Dieter P, Hermann R, Woort-Menker M, Becker H, Schaefer HE, Decker K (1988) Rat hepatic sinusoidal endothelial cells in monolayer culture. Biochemical and ultrastructural characteristics. J Hepatol 6:23–35

Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101:890–898

Fagerholm U (2007) Prediction of human pharmacokinetics–evaluation of methods for prediction of hepatic metabolic clearance. J Pharm Pharmacol 59:803–828

Fahmi OA, Hurst S, Plowchalk D, Cook J, Guo F, Youdim K, Dickins M, Phipps A, Darekar A, Hyland R, Obach RS (2009) Comparison of different algorithms for predicting clinical drug-drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction. Drug Metab Dispos 37:1658–1666

Fahrmayr C, Fromm MF, Konig J (2010) Hepatic OATP and OCT uptake transporters: their role for drug-drug interactions and pharmacogenetic aspects. Drug Metab Rev 42:380–401

Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benyon RC, Duffield JS, Iredale JP (2007) Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 178:5288–5295

Fan L, Tu X, Zhu Y, Zhou L, Pfeiffer T, Feltens R, Stoecker W, Zhong R (2005) Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. J Gastroenterol Hepatol 20:249–255

Fan J, Liu S, Du Y, Morrison J, Shipman R, Pang KS (2009) Up-regulation of transporters and enzymes by the vitamin D receptor ligands, 1alpha,25-dihydroxyvitamin D3 and vitamin D analogs, in the Caco-2 cell monolayer. J Pharmacol Exp Ther 330:389–402

Fan J, Shang Y, Yuan Y, Yang J (2010) Preparation and characterization of chitosan/galactosylated hyaluronic acid scaffolds for primary hepatocytes culture. J Mater Sci Mater Med 21:319–327

Fan Y, Boivin GP, Knudsen ES, Nebert DW, Xia Y, Puga A (2010) The aryl hydrocarbon receptor functions as a tumor suppressor of liver carcinogenesis. Cancer Res 70:212–220

Fandy TE (2009) Development of DNA methyltransferase inhibitors for the treatment of neoplastic diseases. Curr Med Chem 16:2075–2085

Fardel O, Ratanasavanh D, Loyer P, Ketterer B, Guillouzo A (1992) Overexpression of the multidrug resistance gene product in adult rat hepatocytes during primary culture. Eur J Biochem 205:847–852

Fardel O, Morel F, Guillouzo A (1993) P-glycoprotein expression in human, mouse, hamster and rat hepatocytes in primary culture. Carcinogenesis 14:781–783

Fattore E, Trossvik C, Hakansson H (2000) Relative potency values derived from hepatic vitamin A reduction in male and female Sprague-Dawley rats following subchronic dietary exposure to individual polychlorinated dibenzo-p-dioxin and dibenzofuran congeners and a mixture thereof. Toxicol Appl Pharmacol 165:184–194

Faucette SR, Zhang TC, Moore R, Sueyoshi T, Omiecinski CJ, Lecluyse EL, Negishi M, Wang H (2007) Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther 320:72–80

Faulkner L, Martinsson K, Santoyo-Castelazo A, Cederbrant K, Schuppe-Koistinen I, Powell H, Tugwood J, Naisbitt DJ, Park BK (2012) The development of in vitro culture methods to characterize primary T-cell responses to drugs. Toxicol Sci 127:150–158

Fausto N (2004) Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39:1477–87

FDA FADA (2012) Guidance for industry: drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations

Fedorovich NE, Schuurman W, Wijnberg HM, Prins HJ, van Weeren PR, Malda J, Alblas J, Dhert WJ (2012) Biofabrication of osteochondral tissue equivalents by printing topologically defined, cell-laden hydrogel scaffolds. Tissue Eng Part C Methods 18:33–44

Feige JN, Gelman L, Tudor C, Engelborghs Y, Wahli W, Desvergne B (2005) Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator-activated receptor/retinoid X receptor heterodimers in the absence and presence of ligand. J Biol Chem 280:17880–17890

Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ (2003) Hepatocyte apoptosis and Fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125:437–443

Feng B, Xu JJ, Bi YA, Mireles R, Davidson R, Duignan DB, Campbell S, Kostrubsky VE, Dunn MC, Smith AR, Wang HF (2009) Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714. Toxicol Sci 108:492–500

Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, Cain K, Macfarlane M, Hacker G, Leverkus M (2011) cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell 43:449–463

Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ (1996) Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 140:173–179

Ferreira KS, Kreutz C, Macnelly S, Neubert K, Haber A, Bogyo M, Timmer J, Borner C (2012) Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes. Apoptosis 17:503–515

Ferry N, Duplessis O, Houssin D, Danos O, Heard JM (1991) Retroviral-mediated gene transfer into hepatocytes in vivo. Proc Natl Acad Sci USA 88:8377–8381

Fickert P, Fuchsbichler A, Moustafa T, Wagner M, Zollner G, Halilbasic E, Stoger U, Arrese M, Pizarro M, Solis N, Carrasco G, Caligiuri A, Sombetzki M, Reisinger E, Tsybrovskyy O, Zatloukal K, Denk H, Jaeschke H, Pinzani M, Trauner M (2009) Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. Am J Pathol 175:2392–23405

Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A, Riccardi L, Orlandi S, Pellicciari R, Morelli A (2004) The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127:1497–1512

Fiorucci S, Cipriani S, Mencarelli A, Renga B, Distrutti E, Baldelli F (2010) Counter-regulatory role of bile acid activated receptors in immunity and inflammation. Curr Mol Med 10:579–595

Fisher R, Ulreich JB, Nakazato PZ, Brendel K (2001) Histological and biochemical evaluation of precision-cut liver slices. Toxicol Methods (Taylor & Francis, 2001) 11

Fletcher J, Cui W, Samuel K, Black JR, Hannoun Z, Currie IS, Terrace JD, Payne C, Filippi C, Newsome P, Forbes SJ, Ross JA, Iredale JP, Hay DC (2008) The inhibitory role of stromal cell mesenchyme on human embryonic stem cell hepatocyte differentiation is overcome by Wnt3a treatment. Cloning Stem Cells 10:331–339

Fonsato V, Herrera MB, Buttiglieri S, Gatti S, Camussi G, Tetta C (2010) Use of a rotary bioartificial liver in the differentiation of human liver stem cells. Tissue Eng Part C Methods 16:123–132

Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RM, Weinberger C (1995) Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81:687–693

Forman BM, Tzameli I, Choi HS, Chen J, Simha D, Seol W, Evans RM, Moore DD (1998) Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 395:612–615

Foster JA, Houston JB, Hallifax D (2012) Comparison of intrinsic clearances in human liver microsomes and suspended hepatocytes from the same donor livers: clearance-dependent relationship and implications for prediction of in vivo clearance. Xenobiotica 41:124–136

Foty RA, Steinberg MS (2005) The differential adhesion hypothesis: a direct evaluation. Dev Biol 278:255–263

Fox TR, Best LL, Goldsworthy SM, Mills JJ, Goldsworthy TL (1993) Gene expression and cell proliferation in rat liver after 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure. Cancer Res 53:2265–22671

Fraczek J, Deleu S, Lukaszuk A, Doktorova T, Tourwe D, Geerts A, Vanhaecke T, Vanderkerken K, Rogiers V (2009) Screening of amide analogues of Trichostatin A in cultures of primary rat hepatocytes: search for potent and safe HDAC inhibitors. Invest New Drugs 27:338–346

Fraczek JE, Vinken M, Tourwe D, Vanhaecke T, Rogiers V (2011) Synergetic effects of DNA demethylation and histone deacetylase inhibition in primary rat hepatocytes. Invest New Drugs 30:1715–1724

Frederick DM, Jacinto EY, Patel NN, Rushmore TH, Tchao R, Harvison PJ (2011) Cytotoxicity of 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT) and analogues in wild type and CYP3A4 stably transfected HepG2 cells. Toxicol In Vitro 25:2113–2139

Friedman SL (2004) Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 1:98–105

Friedman SL (2008) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125–172

Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA (2009) Spheroid-based drug screen: considerations and practical approach. Nat Protoc 4:309–324

Fromm MF, Kauffmann HM, Fritz P, Burk O, Kroemer HK, Warzok RW, Eichelbaum M, Siegmund W, Schrenk D (2000) The effect of rifampin treatment on intestinal expression of human MRP transporters. Am J Pathol 157:1575–1580

Fukai F, Suzuki Y, Nishizawa Y, Katayama T (1996) Transcellular biosynthesis of cysteinyl leukotrienes by Kupffer cell-hepatocyte cooperation in rat liver. Cell Biol Int 20:423–428

Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T (2003) The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278:4035–4040

Fukuda J, Nakazawa K (2011) Hepatocyte spheroid arrays inside microwells connected with microchannels. Biomicrofluidics 5:22205

Fukuda J, Sakai Y, Nakazawa K (2006) Novel hepatocyte culture system developed using microfabrication and collagen/polyethylene glycol microcontact printing. Biomaterials 27:1061–1070

Fukushima K, Ichimiya H, Higashijima H, Yamashita H, Kuroki S, Chijiiwa K, Tanaka M (1995) Regulation of bile acid synthesis in the rat: relationship between hepatic cholesterol 7 alpha-hydroxylase activity and portal bile acids. J Lipid Res 36:315–321

Funaoka M, Komatsu M, Toyoshima I, Mikami K, Ono T, Hoshino T, Kato J, Kuramitsu T, Ishii T, Masamune O (1999) Tauroursodeoxycholic acid enhances phagocytosis of the cultured rat Kupffer cell. J Gastroenterol Hepatol 14:652–628

Funatsu K, Ijima H, Nakazawa K, Yamashita Y, Shimada M, Sugimachi K (2001) Hybrid artificial liver using hepatocyte organoid culture. Artif Organs 25:194–200

Funk C (2008) The role of hepatic transporters in drug elimination. Expert Opin Drug Metab Toxicol 4:363–379

Gabay C, Kushner I (1999) Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448–454

Gabele E, Muhlbauer M, Dorn C, Weiss TS, Froh M, Schnabl B, Wiest R, Scholmerich J, Obermeier F, Hellerbrand C (2008) Role of TLR9 in hepatic stellate cells and experimental liver fibrosis. Biochem Biophys Res Commun 376:271–276

Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, Klomp LW, Siersema PD, Schipper ME, Danese S, Penna G, Laverny G, Adorini L, Moschetta A, van Mil SW (2011) Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60:463–472

Galbiati G, Muraca M, Mitry RR, Hughes RD, Lehec SC, Puppi J, Sagias FG, Caruso M, Mieli-Vergani G, Dhawan A (2010) Bilirubin, a physiological antioxidant, can improve cryopreservation of human hepatocytes. J Pediatr Gastroenterol Nutr 50:691–693

Galle J, Loeffler M, Drasdo D (2005) Modeling the effect of deregulated proliferation and apoptosis on the growth dynamics of epithelial cell populations in vitro. Biophys J 88:62–75

Gallenne T, Gautier F, Oliver L, Hervouet E, Noel B, Hickman JA, Geneste O, Cartron PF, Vallette FM, Manon S, Juin P (2009) Bax activation by the BH3-only protein Puma promotes cell dependence on antiapoptotic Bcl-2 family members. J Cell Biol 185:279–290

Gandhi A, Guo T, Ghose R (2010) Role of c-Jun N-terminal kinase (JNK) in regulating tumor necrosis factor-alpha (TNF-alpha) mediated increase of acetaminophen (APAP) and chlorpromazine (CPZ) toxicity in murine hepatocytes. J Toxicol Sci 35:163–173

Gao J, Ann Garulacan J, Storm SM, Hefta SA, Opiteck GJ, Lin JH, Moulin F, Dambach DM (2004) Identification of in vitro protein biomarkers of idiosyncratic liver toxicity. Toxicol In Vitro 18:533–541

Gardemann A, Jahns U, Jungermann K (1991) Control of glycogenolysis and blood flow by arterial and portal norepinephrine in perfused liver. Am J Physiol 260:E762–E771

Gardner OS, Dewar BJ, Earp HS, Samet JM, Graves LM (2003) Dependence of peroxisome proliferator-activated receptor ligand-induced mitogen-activated protein kinase signaling on epidermal growth factor receptor transactivation. J Biol Chem 278:46261–46269

Gascon-Barre M, Demers C, Mirshahi A, Neron S, Zalzal S, Nanci A (2003) The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology 37:1034–1042

Gaudio E, Carpino G, Cardinale V, Franchitto A, Onori P, Alvaro D (2009) New insights into liver stem cells. Dig Liver Dis 41:455–462

Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, Tu HC, Kim H, Cheng EH, Tjandra N, Walensky LD (2008) BAX activation is initiated at a novel interaction site. Nature 455:1076–1081

Ge NL, Elferink CJ (1998) A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle. J Biol Chem 273:22708–22713

Gebhardt R (1992) Metabolic zonation of the liver: regulation and implications for liver function. Pharmacol Ther 53:275–354

Gebhardt R (1998) Isolation of periportal and pericentral hepatocytes. In: Phillips IR, Shephard EA (eds) Methods in molecular biology, Vol 107: cytochrome P450 protocols. Humana Press Inc., Totowa, NJ, pp 319–328

Gebhardt R (2002) Co-cultivation of liver epithelial cells with hepatocytes. Methods Mol Biol 188:337–346

Gebhardt R, Mecke D (1979) Permissive effect of dexamethasone on glucagon induction of urea-cycle enzymes in perifused primary monolayer cultures of rat hepatocytes. Eur J Biochem 97:29–35

Gebhardt R, Mecke D (1979) Perifused monolayer cultures of rat hepatocytes as an improved in vitro system for studies on ureogenesis. Exp Cell Res 124:349–359

Gebhardt R, Mecke D (1983) Heterogeneous distribution of glutamine synthetase among rat liver parenchymal cells in situ and in primary culture. Embo J 2:567–570

Gebhardt R, Jonitza D (1991) Different proliferative responses of periportal and perivenous hepatocytes to EGF. Biochem Biophys Res Commun 181:1201–1207

Gebhardt R, Fischer S (1995) Enhanced sensitivity of perifused primary rat hepatocytes to mitogens and growth modulation by carcinogens. Toxicol In Vitro 9:445–451

Gebhardt R, Gaunitz F (1997) Cell-cell interactions in the regulation of the expression of hepatic enzymes. Cell Biol Toxicol 13:263–273

Gebhardt R, Ueberham E (2006) Zonal gene expression in murine liver: are tumors helping us to solve the mystery? Hepatology 44: 512; author reply 512–513

Gebhardt R, Hovhannisyan A (2010) Organ patterning in the adult stage: the role of Wnt/beta-catenin signaling in liver zonation and beyond. Dev Dyn 239:45–55

Gebhardt R, Wegner H, Alber J (1996) Perifusion of co-cultured hepatocytes: optimization of studies on drug metabolism and cytotoxicity in vitro. Cell Biol Toxicol 12:57–68

Gebhardt R, Schuler M, Schorner D (1998) The spontaneous induction of glutamine synthetase in pig hepatocytes cocultured with RL-ET-14 cells is completely inhibited by trijodothyronine and okadaic acid. Biochem Biophys Res Commun 246:895–898

Gebhardt R, Hengstler JG, Muller D, Glockner R, Buenning P, Laube B, Schmelzer E, Ullrich M, Utesch D, Hewitt N, Ringel M, Hilz BR, Bader A, Langsch A, Koose T, Burger HJ, Maas J, Oesch F (2003) New hepatocyte in vitro systems for drug metabolism: metabolic capacity and recommendations for application in basic research and drug development, standard operation procedures. Drug Metab Rev 35:145–213

Geick A, Eichelbaum M, Burk O (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276:14581–14587

Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82

Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327:656–661

George CL, Lightman SL, Biddie SC (2011) Transcription factor interactions in genomic nuclear receptor function. Epigenomics 3:471–85

Gerbal-Chaloin S, Daujat M, Pascussi JM, Pichard-Garcia L, Vilarem MJ, Maurel P (2002) Transcriptional regulation of CYP2C9 gene. Role of glucocorticoid receptor and constitutive androstane receptor. J Biol Chem 277:209–217

Gerlach JC, Brombacher J, Kloppel K, Schnoy N, Neuhaus P (1994) Comparison of four methods for mass hepatocyte isolation from pig and human livers. Transplantation 57:1318–22

Gerloff T, Meier PJ, Stieger B (1998) Taurocholate induces preferential release of phosphatidylcholine from rat liver canalicular vesicles. Liver 18:306–312

Ghent CN, Carruthers SG (1988) Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial. Gastroenterology 94:488–493

Ghodsizadeh A, Taei A, Totonchi M, Seifinejad A, Gourabi H, Pournasr B, Aghdami N, Malekzadeh R, Almadani N, Salekdeh GH, Baharvand H (2010) Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Stem Cell Rev 6:622–632

Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236

Giera S, Braeuning A, Kohle C, Bursch W, Metzger U, Buchmann A, Schwarz M (2010) Wnt/beta-catenin signaling activates and determines hepatic zonal expression of glutathione S-transferases in mouse liver. Toxicol Sci 115:22–33

Gille C, Bolling C, Hoppe A, Bulik S, Hoffmann S, Hubner K, Karlstadt A, Ganeshan R, Konig M, Rother K, Weidlich M, Behre J, Holzhutter HG (2010) HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology. Mol Syst Biol 6:411

Gillette BM, Rossen NS, Das N, Leong D, Wang M, Dugar A, Sia SK (2011) Engineering extracellular matrix structure in 3D multiphase tissues. Biomaterials 32:8067–8076

Glaeser H, Bailey DG, Dresser GK, Gregor JC, Schwarz UI, McGrath JS, Jolicoeur E, Lee W, Leake BF, Tirona RG, Kim RB (2007) Intestinal drug transporter expression and the impact of grapefruit juice in humans. Clin Pharmacol Ther 81:362–370

Glaser SS, Gaudio E, Miller T, Alvaro D, Alpini G (2009) Cholangiocyte proliferation and liver fibrosis. Expert Rev Mol Med 11:e7

Glicklis R, Shapiro L, Agbaria R, Merchuk JC, Cohen S (2000) Hepatocyte behavior within three-dimensional porous alginate scaffolds. Biotechnol Bioeng 67:344–353

Gnerre C, Blattler S, Kaufmann MR, Looser R, Meyer UA (2004) Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene. Pharmacogenetics 14:635–645

Gobinet J, Auzou G, Nicolas JC, Sultan C, Jalaguier S (2001) Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP. Biochemistry 40:15369–15377

Godoy P, Hengstler JG, Ilkavets I, Meyer C, Bachmann A, Muller A, Tuschl G, Mueller SO, Dooley S (2009) Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor beta-induced apoptosis. Hepatology 49:2031–2043

Godoy P, Schug M, Bauer A, Hengstler JG (2010) Reversible manipulation of apoptosis sensitivity in cultured hepatocytes by matrix-mediated manipulation of signaling activities. Methods Mol Biol 640:139–155

Gohla A, Klement K, Piekorz RP, Pexa K, Vom Dahl S, Spicher K, Dreval V, Häussinger D, Birnbaumer L, Nurnberg B (2007) An obligatory requirement for the heterotrimeric G protein Gi3 in the antiautophagic action of insulin in the liver. Proc Natl Acad Sci USA 104:3003–3008

Goldin RD, Ratnayaka ID, Breach CS, Brown IN, Wickramasinghe SN (1996) Role of macrophages in acetaminophen (paracetamol)-induced hepatotoxicity. J Pathol 179:432–435

Goldring CE, Kitteringham NR, Jenkins R, Lovatt CA, Randle LE, Abdullah A, Owen A, Liu X, Butler PJ, Williams DP, Metcalfe P, Berens C, Hillen W, Foster B, Simpson A, McLellan L, Park BK (2006) Development of a transactivator in hepatoma cells that allows expression of phase I, phase II, and chemical defense genes. Am J Physiol Cell Physiol 290:C104–C115

Gomez-Duran A, Carvajal-Gonzalez JM, Mulero-Navarro S, Santiago-Josefat B, Puga A, Fernandez-Salguero PM (2009) Fitting a xenobiotic receptor into cell homeostasis: how the dioxin receptor interacts with TGFbeta signaling. Biochem Pharmacol 77:700–712

Gomez-Lechón MJ, Lopez P, Castell JV (1984) Biochemical functionality and recovery of hepatocytes after deep freezing storage. In Vitro 20:826–832

Gomez-Lechón MJ, Jover R, Donato T, Ponsoda X, Rodriguez C, Stenzel KG, Klocke R, Paul D, Guillen I, Bort R, Castell JV (1998) Long-term expression of differentiated functions in hepatocytes cultured in three-dimensional collagen matrix. J Cell Physiol 177:553–562

Gomez-Lechón MJ, Donato MT, Castell JV, Jover R (2003) Human hepatocytes as a tool for studying toxicity and drug metabolism. Curr Drug Metab 4:292–312

Gomez-Lechón MJ, Lahoz A, Jimenez N, V J, Donato MT (2006) Cryopreservation of rat, dog and human hepatocytes: influence of preculture and cryoprotectants on recovery, cytochrome P450 activities and induction upon thawing. Xenobiotica 36:457–472

Gomez-Lechón MJ, Lahoz A, Jimenez N, Bonora A, Castell JV, Donato MT (2008) Evaluation of drug-metabolizing and functional competence of human hepatocytes incubated under hypothermia in different media for clinical infusion. Cell Transplant 17:887–897

Gomez-Lechón MJ, Castell JV, Donato MT (2010) The use of hepatocytes to investigate drug toxicity. Methods Mol Biol 640:389–415

Gomez-Lechón MJ, Lahoz A, Gombau L, Castell JV, Donato MT (2010) In vitro evaluation of potential hepatotoxicity induced by drugs. Curr Pharm Des 16:1963–1977

Gonzalez FJ, Aoyama T, Gelboin HV (1991) Expression of mammalian cytochrome P450 using vaccinia virus. Methods Enzymol 206:85–92

Gonzalez FJ, Kimura S, Tamura S, Gelboin HV (1991) Expression of mammalian cytochrome P450 using baculovirus. Methods Enzymol 206:93–99

Gonzalez FJ, Korzekwa KR (1995) Cytochromes P450 expression systems. Annu Rev Pharmacol Toxicol 35:369–390

Gonzalez FJ, Fernandez-Salaguero P (1998) The aryl hydrocarbon receptor: studies using the AHR-null mice. Drug Metab Dispos 26:1194–1198

Gonzalez FJ, Fernandez-Salguero P, Ward JM (1996) The role of the aryl hydrocarbon receptor in animal development, physiological homeostasis and toxicity of TCDD. J Toxicol Sci 21:273–277

Gonzalez HE, Eugenin EA, Garces G, Solis N, Pizarro M, Accatino L, Saez JC (2002) Regulation of hepatic connexins in cholestasis: possible involvement of Kupffer cells and inflammatory mediators. Am J Physiol Gastrointest Liver Physiol 282:G991–G1001

Gonzalo T, Beljaars L, van de Bovenkamp M, Temming K, van Loenen AM, Reker-Smit C, Meijer DK, Lacombe M, Opdam F, Keri G, Orfi L, Poelstra K, Kok RJ (2007) Local inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cells. J Pharmacol Exp Ther 321:856–865

Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6:517–526

Goodwin B, Redinbo MR, Kliewer SA (2002) Regulation of cyp3a gene transcription by the pregnane x receptor. Annu Rev Pharmacol Toxicol 42:1–23

Goodwin B, Gauthier KC, Umetani M, Watson MA, Lochansky MI, Collins JL, Leitersdorf E, Mangelsdorf DJ, Kliewer SA, Repa JJ (2003) Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor. Proc Natl Acad Sci USA 100:223–228

Goral VN, Hsieh YC, Petzold ON, Clark JS, Yuen PK, Faris RA (2010) Perfusion-based microfluidic device for three-dimensional dynamic primary human hepatocyte cell culture in the absence of biological or synthetic matrices or coagulants. Lab Chip 10:3380–6

Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35

Gore SD (2009) In vitro basis for treatment with hypomethylating agents and histone deacetylase inhibitors: can epigenetic changes be used to monitor treatment? Leuk Res 33(Suppl 2):S2–S6

Goren I, Allmann N, Yogev N, Schurmann C, Linke A, Holdener M, Waisman A, Pfeilschifter J, Frank S (2009) A transgenic mouse model of inducible macrophage depletion: effects of diphtheria toxin-driven lysozyme M-specific cell lineage ablation on wound inflammatory, angiogenic, and contractive processes. Am J Pathol 175:132–147

Gores GJ, Kost LJ, Larusso NF (1986) The isolated perfused rat liver: conceptual and practical considerations. Hepatology 6:511–517

Goulet F, Normand C, Morin O (1988) Cellular interactions promote tissue-specific function, biomatrix deposition and junctional communication of primary cultured hepatocytes. Hepatology 8:1010–1018

Gradhand U, Lang T, Schaeffeler E, Glaeser H, Tegude H, Klein K, Fritz P, Jedlitschky G, Kroemer HK, Bachmakov I, Anwald B, Kerb R, Zanger UM, Eichelbaum M, Schwab M, Fromm MF (2008) Variability in human hepatic MRP4 expression: influence of cholestasis and genotype. Pharmacogenomics J 8:42–52

Graf D, Bode J (2012) Modulation of innate immunity and inflammation by bile acids and their receptors. In: Häussinger D, Keitel V, Kubitz R (eds) Hepatobiliary transport in health and disease. DeGruyter Publishing, Berlin, pp 103–116

Graham MJ, Lucier GW, Linko P, Maronpot RR, Goldstein JA (1988) Increases in cytochrome P-450 mediated 17 beta-estradiol 2-hydroxylase activity in rat liver microsomes after both acute administration and subchronic administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin in a two-stage hepatocarcinogenesis model. Carcinogenesis 9:1935–1941

Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629

Gridelli B, Vizzini G, Pietrosi G, Luca A, Spada M, Gruttadauria S, Cintorino D, Amico G, Chinnici C, Miki T, Schmelzer E, Conaldi PG, Triolo F, Gerlach JC (2012) Efficient human fetal liver cell isolation protocol based on vascular perfusion for liver cell-based therapy and case report on cell transplantation. Liver Transpl 18:226–237

Griffin SJ, Houston JB (2004) Comparison of fresh and cryopreserved rat hepatocyte suspensions for the prediction of in vitro intrinsic clearance. Drug Metab Dispos 32:552–558

Griffith LG, Wu B, Cima MJ, Powers MJ, Chaignaud B, Vacanti JP (1997) In vitro organogenesis of liver tissue. Ann N Y Acad Sci 831:382–397

Griffiths GJ, Dubrez L, Morgan CP, Jones NA, Whitehouse J, Corfe BM, Dive C, Hickman JA (1999) Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis. J Cell Biol 144:903–914

Grime K, Webborn PJ, Riley RJ (2008) Functional consequences of active hepatic uptake on cytochrome P450 inhibition in rat and human hepatocytes. Drug Metab Dispos 36:1670–1678

Grisham JW (1997) Interspecies comparison of liver carcinogenesis: implications for cancer risk assessment. Carcinogenesis 18:59–81

Grondin M, Hamel F, Averill-Bates DA, Sarhan F (2009) Wheat proteins improve cryopreservation of rat hepatocytes. Biotechnol Bioeng 103:582–591

Groothuis GM, Hardonk MJ, Keulemans KP, Nieuwenhuis P, Meijer DK (1982) Autoradiographic and kinetic demonstration of acinar heterogeneity of taurocholate transport. Am J Physiol 243(6):G455–G462

Groothuis GM, Keulemans KP, Hardonk MJ, Meijer DK (1983) Acinar heterogeneity in hepatic transport of dibromosulfophthalein and ouabain studied by autoradiography, normal and retrograde perfusions and computer simulation. Biochem Pharmacol 32(20):3069–3078

Grover A, Benet LZ (2010) Transporter-based drug–drug interactions and their effect on distribution volumes. Springer, Berlin

Guguen-Guillouzo C, Guillouzo A (2010) General review on in vitro hepatocyte models and their applications. Methods Mol Biol 640:1–40

Guguen-Guillouzo C, Campion JP, Brissot P, Glaise D, Launois B, Bourel M, Guillouzo A (1982) High yield preparation of isolated human adult hepatocytes by enzymatic perfusion of the liver. Cell Biol Int Rep 6:625–628

Guguen-Guillouzo C, Clement B, Baffet G, Beaumont C, Morel-Chany E, Glaise D, Guillouzo A (1983) Maintenance and reversibility of active albumin secretion by adult rat hepatocytes co-cultured with another liver epithelial cell type. Exp Cell Res 143:47–54

Guicciardi ME, Gores GJ (2009) Life and death by death receptors. Faseb J 23:1625–1637

Guillouzo A, Corlu A, Aninat C, Glaise D, Morel F, Guguen-Guillouzo C (2007) The human hepatoma HepaRG cells: a highly differentiated model for studies of liver metabolism and toxicity of xenobiotics. Chem Biol Interact 168:66–73

Guillouzo A, Rialland L, Fautrel A, Guyomard C (1999) Survival and function of isolated hepatocytes after cryopreservation. Chem Biol Interact 121:7–16

Gunther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF, Becker C (2011) Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature 477:335–339

Guo C, Sah JF, Beard L, Willson JK, Markowitz SD, Guda K (2008) The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Genes Chromosomes Cancer 47:939–946

Guo GL, Lambert G, Negishi M, Ward JM, Brewer HB Jr, Kliewer SA, Gonzalez FJ, Sinal CJ (2003) Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. J Biol Chem 278:45062–45071

Guyot C, Lepreux S, Combe C, Sarrazy V, Billet F, Balabaud C, Bioulac-Sage P, Desmouliere A (2010) Fibrogenic cell phenotype modifications during remodelling of normal and pathological human liver in cultured slices. Liver Int 30:1529–1540

Guyot C, Stieger B (2011) Interaction of bile salts with rat canalicular membrane vesicles: evidence for bile salt resistant microdomains. J Hepatol 55:1368–1376

Hadi M, Chen Y, Starokozhko V, Merema MT, Groothuis GM (2012) Mouse precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury. Chem Res Toxicol 25(9):1938–1947

Hadi M, Westra IM, Starokozhko V, Dragovic S, Merema MT, Groothuis GM (2013) Human precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury. Chem Res Toxicol 26(5):710–720

Haenisch S, Laechelt S, Bruckmueller H, Werk A, Noack A, Bruhn O, Remmler C, Cascorbi I (2011) Down-regulation of ATP-binding cassette C2 protein expression in HepG2 cells after rifampicin treatment is mediated by microRNA-379. Mol Pharmacol 80:314–320

Hagenbuch B, Gui C (2008) Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 38:778–801

Hagenbuch B, Meier PJ (1994) Molecular cloning, chromosomal localization, and functional characterization of a human liver Na +/bile acid cotransporter. J Clin Invest 93:1326–1331

Hagenbuch B, Meier PJ (2004) Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch 447:653–665

Hagenbuch B, Scharschmidt BF, Meier PJ (1996) Effect of antisense oligonucleotides on the expression of hepatocellular bile acid and organic anion uptake systems in Xenopus laevis oocytes. Biochem J 316(Pt 3):901–904

Hagenbuch B, Stieger B, Foguet M, Lubbert H, Meier PJ (1991) Functional expression cloning and characterization of the hepatocyte Na +/bile acid cotransport system. Proc Natl Acad Sci USA 88:10629–10633

Hagens WI, Olinga P, Meijer DK, Groothuis GM, Beljaars L, Poelstra K (2006) Gliotoxin non-selectively induces apoptosis in fibrotic and normal livers. Liver Int 26:232–239

Haggart CR, Bartell JA, Saucerman JJ, Papin JA (2011) Whole-genome metabolic network reconstruction and constraint-based modeling. Methods Enzymol 500:411–433

Hailey JR, Walker NJ, Sells DM, Brix AE, Jokinen MP, Nyska A (2005) Classification of proliferative hepatocellular lesions in Harlan Sprague-Dawley rats chronically exposed to dioxin-like compounds. Toxicol Pathol 33:165–174

Hailfinger S, Jaworski M, Braeuning A, Buchmann A, Schwarz M (2006) Zonal gene expression in murine liver: lessons from tumors. Hepatology 43:407–414

Hakansson H, Hanberg A (1989) The distribution of [14C]-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its effect on the vitamin A content in parenchymal and stellate cells of rat liver. J Nutr 119:573–580

Hallifax D, Foster JA, Houston JB (2010) Prediction of human metabolic clearance from in vitro systems: retrospective analysis and prospective view. Pharm Res 27:2150–2161

Hallifax D, Houston JB (2006) Uptake and intracellular binding of lipophilic amine drugs by isolated rat hepatocytes and implications for prediction of in vivo metabolic clearance. Drug Metab Dispos 34:1829–1836

Hallifax D, Houston JB (2009) Methodological uncertainty in quantitative prediction of human hepatic clearance from in vitro experimental systems. Curr Drug Metab 10:307–321

Hallifax D, Foster JA, Houston JB (2010) Prediction of human metabolic clearance from in vitro systems: retrospective analysis and prospective view. Pharm Res 27:2150–2161

Hallifax D, Houston JB (2012) Evaluation of hepatic clearance prediction using in vitro data: Emphasis on fraction unbound in plasma and drug ionisation using a database of 107 drugs. J Pharm Sci 101:2645–2652

Hallifax D, Turlizzi E, Zanelli U, Houston JB (2012) Clearance-dependent underprediction of in vivo intrinsic clearance from human hepatocytes: comparison with permeabilities from artificial membrane (PAMPA) assay, in silico and caco-2 assay, for 65 drugs. Eur J Pharm Sci 45:570–574

Halliwell B (2003) Oxidative stress in cell culture: an under-appreciated problem? FEBS Lett 540:3–6

Halmos B, Szalay F, Cserniczky T, Nemesanszky E, Lakatos P, Barlage S, Schmitz G, Romics L, Csaszar A (2000) Association of primary biliary cirrhosis with vitamin D receptor BsmI genotype polymorphism in a Hungarian population. Dig Dis Sci 45:1091–1095

Hamada A, Sissung T, Price DK, Danesi R, Chau CH, Sharifi N, Venzon D, Maeda K, Nagao K, Sparreboom A, Mitsuya H, Dahut WL, Figg WD (2008) Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in Caucasian patients with androgen-independent prostatic cancer. Clin Cancer Res 14:3312–3318

Hamada E, Nishida T, Uchiyama Y, Nakamura J, Isahara K, Kazuo H, Huang TP, Momoi T, Ito T, Matsuda H (1999) Activation of Kupffer cells and caspase-3 involved in rat hepatocyte apoptosis induced by endotoxin. J Hepatol 30:807–818

Hamadeh HK, Bushel PR, Jayadev S, Disorbo O, Bennett L, Li L, Tennant R, Stoll R, Barrett JC, Paules RS, Blanchard K, Afshari CA (2002) Prediction of compound signature using high density gene expression profiling. Toxicol Sci 67:232–240

Hamadeh HK, Bushel PR, Jayadev S, Martin K, Disorbo O, Sieber S, Bennett L, Tennant R, Stoll R, Barrett JC, Blanchard K, Paules RS, Afshari CA (2002) Gene expression analysis reveals chemical-specific profiles. Toxicol Sci 67:219–231

Hamilton GA, Jolley SL, Gilbert D, Coon DJ, Barros S, Lecluyse EL (2001) Regulation of cell morphology and cytochrome P450 expression in human hepatocytes by extracellular matrix and cell-cell interactions. Cell Tissue Res 306:85–99

Hammond JS, Beckingham IJ, Shakesheff KM (2006) Scaffolds for liver tissue engineering. Expert Rev Med Devices 3:21–27

Han S, Chiang JY (2009) Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes. Drug Metab Dispos 37:469–478

Hanafy S, El-Kadi AO, Jamali F (2012) Effect of inflammation on molecular targets and drug transporters. J Pharm Pharm Sci 15(3):361–375

Hang H, Shi X, Gu G, Wu Y, Gu J, Ding Y (2010) In vitro analysis of cryopreserved alginate-poly-L-lysine-alginate-microencapsulated human hepatocytes. Liver Int 30:611–622

Hardonk MJ, Dijkhuis FW, Hulstaert CE, Koudstaal J (1992) Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation. J Leukoc Biol 52:296–302

Harris CL, Toner M, Hubel A, Cravalho EG, Yarmush ML, Tompkins RG (1991) Cryopreservation of isolated hepatocytes: intracellular ice formation under various chemical and physical conditions. Cryobiology 28:436–444

Hartmann H, Beckh K, Jungermann K (1982) Direct control of glycogen metabolism in the perfused rat liver by the sympathetic innervation. Eur J Biochem 123:521–526

Hasirci V, Berthiaume F, Bondre SP, Gresser JD, Trantolo DJ, Toner M, Wise DL (2001) Expression of liver-specific functions by rat hepatocytes seeded in treated poly(lactic-co-glycolic) acid biodegradable foams. Tissue Eng 7:385–394

Hassoun EA, Li F, Abushaban A, Stohs SJ (2000) The relative abilities of TCDD and its congeners to induce oxidative stress in the hepatic and brain tissues of rats after subchronic exposure. Toxicology 145:103–113

Häussinger D (1983) Hepatocyte heterogeneity in glutamine and ammonia metabolism and the role of an intercellular glutamine cycle during ureogenesis in perfused rat liver. Eur J Biochem 133:269–275

Häussinger D (1986) Urea synthesis and CO2/HCO3- compartmentation in isolated perfused rat liver. Biol Chem Hoppe Seyler 367:741–750

Häussinger D (1987) Isolated perfused rat liver: an experimental model for studies on ammonium and amino acid metabolism. Infusionsther Klin Ernahr 14:174–178

Häussinger D (2012) Bile acid signaling in the liver and the biliary tree. In: Häussinger D, Keitel V, Kubitz R (eds) Hepatobiliary transport in health and disease. DeGruyter Publishing, Berlin, pp 85–102

Häussinger D, Gerok W (1984) Hepatocyte heterogeneity in ammonia metabolism: impairment of glutamine synthesis in CCl4 induced liver cell necrosis with no effect on urea synthesis. Chem Biol Interact 48:191–194

Häussinger D, Stehle T (1988) Hepatocyte heterogeneity in response to eicosanoids. The perivenous scavenger cell hypothesis. Eur J Biochem 175:395–403

Häussinger D, Kaiser S, Stehle T, Gerok W (1986) Liver carbonic anhydrase and urea synthesis. The effect of diuretics. Biochem Pharmacol 35:3317–3322

Häussinger D, Stehle T, Gerok W, Sies H (1987) Perivascular nerve stimulation and phenylephrine responses in rat liver. Metabolic effects, Ca2+ and K+ fluxes. Eur J Biochem 163:197–203

Häussinger D, Kurz AK, Wettstein M, Graf D, Vom DAHLS, Schliess F (2003) Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis. Gastroenterology 124(5):1476–187

Häussinger D, Reinehr R, Keitel V (2012) Bile acid signaling in the liver and the biliary tree. In: Häussinger D, Keitel V, Kubitz R (eds) Hepatobiliary Transport in Health and Disease. DeGruyter Publishing, Berlin, pp 85–102

Haws LC, Su SH, Harris M, Devito MJ, Walker NJ, Farland WH, Finley B, Birnbaum LS (2006) Development of a refined database of mammalian relative potency estimates for dioxin-like compounds. Toxicol Sci 89:4–30

He XX, Chang Y, Meng FY, Wang MY, Xie QH, Tang F, Li PY, Song YH, Lin JS (2011) MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. Oncogene 31:3357–3369

He Y, Sadahiro T, Noh SI, Wang H, Todo T, Chai NN, Klein AS, Wu GD (2009) Flow cytometric isolation and phenotypic characterization of two subsets of ED2(+) (CD163) hepatic macrophages in rats. Hepatol Res 39:1208–1218

Hebbes TR, Thorne AW, Crane-Robinson C (1988) A direct link between core histone acetylation and transcriptionally active chromatin. Embo J 7:1395–1402

Hediger MA, Romero MF, Peng JB, Rolfs A, Takanaga H, Bruford EA (2004) The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins. Introduction. Pflugers Arch 447:465–468

Heinaniemi M, Uski JO, Degenhardt T, Carlberg C (2007) Meta-analysis of primary target genes of peroxisome proliferator-activated receptors. Genome Biol 8:R147

Heise T, Schug M, Storm D, Ellinger-Ziegelbauer H, Ahr HJ, Hellwig B, Rahnenfuhrer J, Ghallab A, Guenther G, Sisnaiske J, Reif R, Godoy P, Mielke H, Gundert-Remy U, Lampen A, Oberemm A, Hengstler JG (2012) In vitro—in vivo correlation of gene expression alterations induced by liver carcinogens. Curr Med Chem 19:1721–1730

Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA (2007) Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87:905–931

Hendriks B, Reichmann E (2002) Wnt signaling: a complex issue. Biol Res 35:277–286

Hengstler JG, Brulport M, Schormann W, Bauer A, Hermes M, Nussler AK, Fandrich F, Ruhnke M, Ungefroren H, Griffin L, Bockamp E, Oesch F, von Mach MA (2005) Generation of human hepatocytes by stem cell technology: definition of the hepatocyte. Expert Opin Drug Metab Toxicol 1:61–74

Hengstler JG, Ringel M, Biefang K, Hammel S, Milbert U, Gerl M, Klebach M, Diener B, Platt KL, Bottger T, Steinberg P, Oesch F (2000) Cultures with cryopreserved hepatocytes: applicability for studies of enzyme induction. Chem Biol Interact 125:51–73

Hengstler JG, Utesch D, Steinberg P, Platt KL, Diener B, Ringel M, Swales N, Fischer T, Biefang K, Gerl M, Bottger T, Oesch F (2000) Cryopreserved primary hepatocytes as a constantly available in vitro model for the evaluation of human and animal drug metabolism and enzyme induction. Drug Metab Rev 32:81–118

Henkens T, Papeleu P, Elaut G, Vinken M, Rogiers V, Vanhaecke T (2007) Trichostatin A, a critical factor in maintaining the functional differentiation of primary cultured rat hepatocytes. Toxicol Appl Pharmacol 218:64–71

Henkens T, Vinken M, Lukaszuk A, Tourwe D, Vanhaecke T, Rogiers V (2008) Differential effects of hydroxamate histone deacetylase inhibitors on cellular functionality and gap junctions in primary cultures of mitogen-stimulated hepatocytes. Toxicol Lett 178:37–43

Herrera MB, Bruno S, Buttiglieri S, Tetta C, Gatti S, Deregibus MC, Bussolati B, Camussi G (2006) Isolation and characterization of a stem cell population from adult human liver. Stem Cells 24:2840–2850

Hespeling U, Jungermann K, Puschel GP (1995) Feedback-inhibition of glucagon-stimulated glycogenolysis in hepatocyte/Kupffer cell cocultures by glucagon-elicited prostaglandin production in Kupffer cells. Hepatology 22:1577–1583

Hewitt NJ (2010) Optimisation of the cryopreservation of primary hepatocytes. Methods Mol Biol 640:83–105

Hewitt NJ, Lechon MJ, Houston JB, Hallifax D, Brown HS, Maurel P, Kenna JG, Gustavsson L, Lohmann C, Skonberg C, Guillouzo A, Tuschl G, Li AP, Lecluyse E, Groothuis GM, Hengstler JG (2007) Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab Rev 39:159–234

Higashiyama H, Kinoshita M, Asano S (2008) Immunolocalization of farnesoid X receptor (FXR) in mouse tissues using tissue microarray. Acta Histochem 110:86–93

Higuchi H, Bronk SF, Takikawa Y, Werneburg N, Takimoto R, El-Deiry W, Gores GJ (2001) The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis. J Biol Chem 276:38610–38618

Hirano M, Maeda K, Hayashi H, Kusuhara H, Sugiyama Y (2005) Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J Pharmacol Exp Ther 314:876–882

Hirata K, Takagi H, Yamamoto M, Matsumoto T, Nishiya T, Mori K, Shimizu S, Masumoto H, Okutani Y (2008) Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study. Pharmacogenomics J 8(1):29–33

Hirohashi T, Suzuki H, Ito K, Ogawa K, Kume K, Shimizu T, Sugiyama Y (1998) Hepatic expression of multidrug resistance-associated protein-like proteins maintained in Eisai hyperbilirubinemic rats. Mol Pharmacol 53:1068–1075

Hirohashi T, Suzuki H, Takikawa H, Sugiyama Y (2000) ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (Mrp3). J Biol Chem 275:2905–2910

Ho CT, Lin RZ, Chang WY, Chang HY, Liu CH (2006) Rapid heterogeneous liver-cell on-chip patterning via the enhanced field-induced dielectrophoresis trap. Lab Chip 6:724–734

Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, Wang Y, Kim RB (2006) Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130:1793–1806

Hochachka PW (1986) Defense strategies against hypoxia and hypothermia. Science 231:234–241

Hoebe KH, Witkamp RF, Fink-Gremmels J, van Miert AS, Monshouwer M (2001) Direct cell-to-cell contact between Kupffer cells and hepatocytes augments endotoxin-induced hepatic injury. Am J Physiol Gastrointest Liver Physiol 280:G720–G728

Hoehme S, Brulport M, Bauer A, Bedawy E, Schormann W, Hermes M, Puppe V, Gebhardt R, Zellmer S, Schwarz M, Bockamp E, Timmel T, Hengstler JG, Drasdo D (2010) Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci USA 107:10371–10376

Hoehme S, Hengstlerb JG, Brulportb M, Schäferc M, Bauerb A, Drasdoa D (2007) Mathematical modelling of liver regeneration after intoxication with CCl4. Chem Biol Interact 168:74–93

Hoffmaster KA, Turncliff RZ, Lecluyse EL, Kim RB, Meier PJ, Brouwer KL (2004) P-glycoprotein expression, localization, and function in sandwich-cultured primary rat and human hepatocytes: relevance to the hepatobiliary disposition of a model opioid peptide. Pharm Res 21:1294–1302

Hofmann AF (2009) The enterohepatic circulation of bile acids in mammals: form and functions. Front Biosci 14:2584–98

Hofmann AF, Small DM (1967) Detergent properties of bile salts: correlation with physiological function. Annu Rev Med 18:333–376

Hogan BL (1999) Morphogenesis. Cell 96:225–233

Hollister SJ (2005) Porous scaffold design for tissue engineering. Nat Mater 4:518–524

Holownia A, Braszko JJ (2004) Tamoxifen cytotoxicity in hepatoblastoma cells stably transfected with human CYP3A4. Biochem Pharmacol 67:1057–1064

Holstein A, Beil W (2009) Oral antidiabetic drug metabolism: pharmacogenomics and drug interactions. Expert Opin Drug Metab Toxicol 5:225–241

Holt MP, Cheng L, Ju C (2008) Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury. J Leukoc Biol 84:1410–1421

Holt MP, Ju C (2006) Mechanisms of drug-induced liver injury. Aaps J 8:E48–E54

Holy CE, Shoichet MS, Davies JE (2000) Engineering three-dimensional bone tissue in vitro using biodegradable scaffolds: investigating initial cell-seeding density and culture period. J Biomed Mater Res 51:376–382

Holzhutter HG (2004) The principle of flux minimization and its application to estimate stationary fluxes in metabolic networks. Eur J Biochem 271:2905–2922

Holzhutter HG, Drasdo D, Preusser T, Lippert J, Henney AM (2012) The virtual liver: a multidisciplinary, multilevel challenge for systems biology. Wiley Interdiscip Rev Syst Biol Med 4:221–235

Hong SR, Lee YM, Akaike T (2003) Evaluation of a galactose-carrying gelatin sponge for hepatocytes culture and transplantation. J Biomed Mater Res A 67:733–741

Hong JY, Lebofsky M, Farhood A, Jaeschke H (2009) Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation. Am J Physiol Gastrointest Liver Physiol 296:G572–G5781

Hosomi H, Akai S, Minami K, Yoshikawa Y, Fukami T, Nakajima M, Yokoi T (2010) An in vitro drug-induced hepatotoxicity screening system using CYP3A4-expressing and gamma-glutamylcysteine synthetase knockdown cells. Toxicol In Vitro 24:1032–1038

Hosomi H, Fukami T, Iwamura A, Nakajima M, Yokoi T (2011) Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation. Drug Metab Dispos 39:1388–1395

Hou YT, Ijima H, Matsumoto S, Kubo T, Takei T, Sakai S, Kawakami K (2010) Effect of a hepatocyte growth factor/heparin-immobilized collagen system on albumin synthesis and spheroid formation by hepatocytes. J Biosci Bioeng 110:208–216

Hou YT, Ijima H, Takei T, Kawakami K (2011) Growth factor/heparin-immobilized collagen gel system enhances viability of transplanted hepatocytes and induces angiogenesis. J Biosci Bioeng 112:265–272

Houston JB (1994) Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 47:1469–1479

Houston JB, Carlile DJ (1997) Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices. Drug Metab Rev 29:891–922

Houston JB, Galetin A (2010) In vitro techniques to study drug-drug interactions of drug metabolism: cytochrome p450. Springer, New York

Houten SM, Volle DH, Cummins CL, Mangelsdorf DJ, Auwerx J (2007) In vivo imaging of farnesoid X receptor activity reveals the ileum as the primary bile acid signaling tissue. Mol Endocrinol 21:1312–323

Howard M, Jiang X, Stolz DB, Hill WG, Johnson JA, Watkins SC, Frizzell RA, Bruton CM, Robbins PD, Weisz OA (2000) Forskolin-induced apical membrane insertion of virally expressed, epitope-tagged CFTR in polarized MDCK cells. Am J Physiol Cell Physiol 279:C375–C382

Howgate EM, Rowland Yeo K, Proctor NJ, Tucker GT, Rostami-Hodjegan A (2006) Prediction of in vivo drug clearance from in vitro data. I: impact of inter-individual variability. Xenobiotica 36:473–497

Hrach J, Mueller SO, Hewitt P (2011) Development of an in vitro liver toxicity prediction model based on longer term primary rat hepatocyte culture. Toxicol Lett 206:189–196

Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang WP, Kirchgessner TG (1999) A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem 274:37161–37168

Hu G, Xu C, Staudinger JL (2010) Pregnane X receptor is SUMOylated to repress the inflammatory response. J Pharmacol Exp Ther 335:342–350

Hu M, Kurobe M, Jeong YJ, Fuerer C, Ghole S, Nusse R, Sylvester KG (2007) Wnt/beta-catenin signaling in murine hepatic transit amplifying progenitor cells. Gastroenterology 133:1579–1591

Hu T, Li C (2010) Convergence between Wnt-beta-catenin and EGFR signaling in cancer. Mol Cancer 9:236

Huang G, Elferink CJ (2005) Multiple mechanisms are involved in Ah receptor-mediated cell cycle arrest. Mol Pharmacol 67:88–96

Huang SM, Stifano T (2006) Drug interaction studies -study design, data analysis, and implications for dosing and labeling—DRAFT. GUIDANCE. FDA—Guidance for Industry

Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY, Chang FY, Lee SD (2002) Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology 35(4):883–889

Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, Chang FY, Lee SD (2003) Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 37(4):924–930

Huang Y, Lu M, Wu H (2004) Antagonizing XIAP-mediated caspase-3 inhibition. Achilles’ heel of cancers? Cancer Cell 5:1–2

Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, Dong B, Huang X, Moore DD (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312:233–236

Huang H, Oizumi S, Kojima N, Niino T, Sakai Y (2007) Avidin-biotin binding-based cell seeding and perfusion culture of liver-derived cells in a porous scaffold with a three-dimensional interconnected flow-channel network. Biomaterials 28:3815–3823

Huang YS, Su WJ, Huang YH, Chen CY, Chang FY, Lin HC, Lee SD (2007) Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury. J Hepatol 47(1):128–134

Huang P, He Z, Ji S, Sun H, Xiang D, Liu C, Hu Y, Wang X, Hui L (2011) Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475:386–389

Hubbard AL, Stieger B, Bartles JR (1989) Biogenesis of endogenous plasma membrane proteins in epithelial cells. Annu Rev Physiol 51:755–770

Hubel A, Conroy M, Darr TB (2000) Influence of preculture on the prefreeze and postthaw characteristics of hepatocytes. Biotechnol Bioeng 71:173–183

Huelsken J, Behrens J (2002) The Wnt signalling pathway. J Cell Sci 115:3977–3978

Hughes MA, Harper N, Butterworth M, Cain K, Cohen GM, Macfarlane M (2009) Reconstitution of the death-inducing signaling complex reveals a substrate switch that determines CD95-mediated death or survival. Mol Cell 35:265–279

Huh D, Hamilton GA, Ingber DE (2011) From 3D cell culture to organs-on-chips. Trends Cell Biol 21:745–754

Huisman MT, Chhatta AA, van Tellingen O, Beijnen JH, Schinkel AH (2005) MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int J Cancer 116:824–829

Huisman MT, Smit JW, Crommentuyn KM, Zelcer N, Wiltshire HR, Beijnen JH, Schinkel AH (2002) Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. Aids 16:2295–22301

Hulot JS, Villard E, Maguy A, Morel V, Mir L, Tostivint I, William-Faltaos D, Fernandez C, Hatem S, Deray G, Komajda M, Leblond V, Lechat P (2005) A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination. Pharmacogenet Genomics 15:277–285

Huls M, van den Heuvel JJ, Dijkman HB, Russel FG, Masereeuw R (2006) ABC transporter expression profiling after ischemic reperfusion injury in mouse kidney. Kidney Int 69:2186–2193

Hunt NC, Shelton RM, Grover L (2009) An alginate hydrogel matrix for the localised delivery of a fibroblast/keratinocyte co-culture. Biotechnol J. 4(5):730–737

Hushka DR, Greenlee WF (1995) 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits DNA synthesis in rat primary hepatocytes. Mutat Res 333:89–99

Hussaini SH, Farrington EA (2007) Idiosyncratic drug-induced liver injury: an overview. Expert Opin Drug Saf 6:673–684

Ieiri I, Higuchi S, Sugiyama Y (2009) Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Expert Opin Drug Metab Toxicol 5(7):703–729

Ijima H (2010) Practical and functional culture technologies for primary hepatocytes. Biochemical Engineering Journal 48:332–336

Ilan Y, Saito H, Thummala NR, Chowdhury NR (1999) Adenovirus-mediated gene therapy of liver diseases. Semin Liver Dis 19:49–59

Imaeda AB, Watanabe A, Sohail MA, Mahmood S, Mohamadnejad M, Sutterwala FS, Flavell RA, Mehal WZ (2009) Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest 119:305–314

Inamori M, Mizumoto H, Kajiwara T (2009) An approach for formation of vascularized liver tissue by endothelial cell-covered hepatocyte spheroid integration. Tissue Eng Part A 15:2029–2037

Inoue C, Yamamoto H, Nakamura T, Ichihara A, Okamoto H (1989) Nicotinamide prolongs survival of primary cultured hepatocytes without involving loss of hepatocyte-specific functions. J Biol Chem 264:4747–4750

Ishida Y, Kondo T, Kimura A, Tsuneyama K, Takayasu T, Mukaida N (2006) Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen-induced acute liver injury. Eur J Immunol 36:1028–1038

Ishigami M, Tokui T, Komai T, Tsukahara K, Yamazaki M, Sugiyama Y (1995) Evaluation of the uptake of pravastatin by perfused rat liver and primary cultured rat hepatocytes. Pharm Res 12:1741–1745

Ishiguro N, Maeda K, Saito A, Kishimoto W, Matsushima S, Ebner T, Roth W, Igarashi T, Sugiyama Y (2008) Establishment of a set of double transfectants coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide. Drug Metab Dispos 36:796–805

Ismair MG, Hausler S, Stuermer CA, Guyot C, Meier PJ, Roth J, Stieger B (2009) ABC-transporters are localized in caveolin-1-positive and reggie-1-negative and reggie-2-negative microdomains of the canalicular membrane in rat hepatocytes. Hepatology 49:1673–1682

Ismair MG, Stieger B, Cattori V, Hagenbuch B, Fried M, Meier PJ, Kullak-Ublick GA (2001) Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver. Gastroenterology 121:1185–1190

Isom HC, Secott T, Georgoff I, Woodworth C, Mummaw J (1985) Maintenance of differentiated rat hepatocytes in primary culture. Proc Natl Acad Sci USA 82:3252–3256

ITC (International Transporter Consortium) (2010) Membrane transporters in drug development (Report from the FDA Critical Path Workshop). Nat Rev Drug Discov 9:215–236

Ito K, Chiba K, Horikawa M, Ishigami M, Mizuno N, Aoki J, Gotoh Y, Iwatsubo T, Kanamitsu S, Kato M, Kawahara I, Niinuma K, Nishino A, Sato N, Tsukamoto Y, Ueda K, Itoh T, Sugiyama Y (2002) Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data? AAPS PharmSci 4:E25

Ito K, Houston JB (2004) Comparison of the use of liver models for predicting drug clearance using in vitro kinetic data from hepatic microsomes and isolated hepatocytes. Pharm Res 21:785–792

Ito K, Houston JB (2005) Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharm Res 22:103–112

Ito K, Suzuki H, Hirohashi T, Kume K, Shimizu T, Sugiyama Y (1997) Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am J Physiol 272:G16–G22

Ito K, Iwatsubo T, Kanamitsu S, Ueda K, Suzuki H, Sugiyama Y (1998) Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. Pharmacol Rev 50:387–412

Ito K, Ogihara K, Kanamitsu S, Itoh T (2003) Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes. Drug Metab Dispos 31:945–54

Ito Y, Bethea NW, Abril ER, McCuskey RS (2003) Early hepatic microvascular injury in response to acetaminophen toxicity. Microcirculation 10:391–400

Ito K, Brown HS, Houston JB (2004) Database analyses for the prediction of in vivo drug-drug interactions from in vitro data. Br J Clin Pharmacol 57:473–486

Ito K, Hallifax D, Obach RS, Houston JB (2005) Impact of parallel pathways of drug elimination and multiple cytochrome P450 involvement on drug-drug interactions: CYP2D6 paradigm. Drug Metab Dispos 33:837–844

Itoh M, Nakajima M, Higashi E, Yoshida R, Nagata K, Yamazoe Y, Yokoi T (2006) Induction of human CYP2A6 is mediated by the pregnane X receptor with peroxisome proliferator-activated receptor-gamma coactivator 1alpha. J Pharmacol Exp Ther 319:693–702

Iwakiri Y, Groszmann RJ (2007) Vascular endothelial dysfunction in cirrhosis. J Hepatol 46:927–934

Iwamura A, Fukami T, Hosomi H, Nakajima M, Yokoi T (2011) CYP2C9-mediated metabolic activation of losartan detected by a highly sensitive cell-based screening assay. Drug Metab Dispos 39(5):838–846

Iwamuro M, Komaki T, Kubota Y, Seita M, Kawamoto H, Yuasa T, Shahid JM, Hassan RA, Hassan WA, Nakaji S, Nishikawa Y, Kondo E, Yamamoto K, Fox IJ, Kobayashi N (2010) Hepatic differentiation of mouse iPS cells in vitro. Cell Transplant 19:841–847

Jacobson L, Middleton B, Holmgren J, Eirefelt S, Frojd M, Blomgren A, Gustavsson L (2007) An optimized automated assay for determination of metabolic stability using hepatocytes: assay validation, variance component analysis, and in vivo relevance. Assay Drug Dev Technol 5:403–415

Jacquemin E, Hagenbuch B, Stieger B, Wolkoff AW, Meier PJ (1994) Expression cloning of a rat liver Na(+)-independent organic anion transporter. Proc Natl Acad Sci USA 91:133–137

Jaeschke H (2003) Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 284:G15–G26

Jaeschke H (2006) Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions. Am J Physiol Gastrointest Liver Physiol 290:G1083–G1088

Jaeschke H (2011) Reactive oxygen and mechanisms of inflammatory liver injury: Present concepts. J Gastroenterol Hepatol 26(Suppl 1):173–179

Jaeschke H, Bajt ML (2006) Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 89:31–41

Jaeschke H, Hasegawa T (2006) Role of neutrophils in acute inflammatory liver injury. Liver Int 26:912–919

Jaeschke H, Liu J (2007) Neutrophil depletion protects against murine acetaminophen hepatotoxicity: another perspective. Hepatology 45:1588–1589; author reply 1589

Jaeschke H, McGill MR, Ramachandran A (2011) Pathophysiological relevance of proteomics investigations of drug-induced hepatotoxicity in HepG2 cells. Toxicol Sci 121:428–430; author reply 431–433

Jaeschke H, McGill MR, Ramachandran A (2012a) Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev 44:88–106

Jaeschke H, Williams CD, Ramachandran A, Bajt ML (2012b) Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int 32:8–20

Jakobsson T, Treuter E, Gustafsson JA, Steffensen KR (2012) Liver X receptor biology and pharmacology: new pathways, challenges and opportunities. Trends Pharmacol Sci 33:394–404

James LP, McCullough SS, Knight TR, Jaeschke H, Hinson JA (2003) Acetaminophen toxicity in mice lacking NADPH oxidase activity: role of peroxynitrite formation and mitochondrial oxidant stress. Free Radic Res 37:1289–1297

Janneh O, Jones E, Chandler B, Owen A, Khoo SH (2007) Inhibition of P-glycoprotein and multidrug resistance-associated proteins modulates the intracellular concentration of lopinavir in cultured CD4 T cells and primary human lymphocytes. J Antimicrob Chemother 60:987–993

Jansen PL (2000) Foreword: from classic bile physiology to cloned transporters. Semin Liver Dis 20:245–2450

Jansen PL, Peters WH, Lamers WH (1985) Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology 5:573–579

Jaworski M, Buchmann A, Bauer P, Riess O, Schwarz M (2005) B-raf and Ha-ras mutations in chemically induced mouse liver tumors. Oncogene 24:1290–1295

Jaworski M, Ittrich C, Hailfinger S, Bonin M, Buchmann A, Schwarz M, Kohle C (2007) Global gene expression in Ha-ras and B-raf mutated mouse liver tumors. Int J Cancer 121:1382–1385

Jemmerson R, Liu J, Hausauer D, Lam KP, Mondino A, Nelson RD (1999) A conformational change in cytochrome c of apoptotic and necrotic cells is detected by monoclonal antibody binding and mimicked by association of the native antigen with synthetic phospholipid vesicles. Biochemistry 38:3599–3609

Jemnitz K, Veres Z, Monostory K, Kobori L, Vereczkey L (2008) Interspecies differences in acetaminophen sensitivity of human, rat, and mouse primary hepatocytes. Toxicol In Vitro 22:961–967

Jemnitz K, Veres Z, Szabo M, Baranyai Z, Jakab F, Vereczkey L (2012) Differential inhibitory effect of cyclosporine A and bosentan on taurocholate uptake in human and rat hepatocytes as a function of culturing time. Toxicol In Vitro 26:174–181

Jerby L, Shlomi T, Ruppin E (2010) Computational reconstruction of tissue-specific metabolic models: application to human liver metabolism. Mol Syst Biol 6:401

Ji S, Lemasters JJ, Thurman RG (1980) A non-invasive method to study metabolic events within sublobular regions of hemoglobin-free perfused liver. FEBS Lett 113:37–42

Jiang G, Nepomuceno L, Hopkins K, Sladek FM (1995) Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors. Mol Cell Biol 15:5131–5143

Jigorel E, Houston JB (2012) Utility of drug depletion-time profiles in isolated hepatocytes for accessing hepatic uptake clearance: identifying rate-limiting steps and role of passive processes. Drug Metab Dispos 40:1596–1602

Jigorel E, le Vee M, Boursier-Neyret C, Parmentier Y, Fardel O (2006) Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Drug Metab Dispos 34:1756–1763

Jindal R, Nahmias Y, Tilles AW, Berthiaume F, Yarmush ML (2009) Amino acid-mediated heterotypic interaction governs performance of a hepatic tissue model. Faseb J 23:2288–2298

Joannard F, Rissel M, Gilot D, Anderson A, Orfila-Lefeuvre L, Guillouzo A, Atfi A, Lagadic-Gossmann D (2006) Role for mitogen-activated protein kinases in phenobarbital-induced expression of cytochrome P450 2B in primary cultures of rat hepatocytes. Toxicol Lett 161:61–72

Johansson L, Thomsen JS, Damdimopoulos AE, Spyrou G, Gustafsson JA, Treuter E (1999) The orphan nuclear receptor SHP inhibits agonist-dependent transcriptional activity of estrogen receptors ERalpha and ERbeta. J Biol Chem 274:345–353

Johansson L, Bavner A, Thomsen JS, Farnegardh M, Gustafsson JA, Treuter E (2000) The orphan nuclear receptor SHP utilizes conserved LXXLL-related motifs for interactions with ligand-activated estrogen receptors. Mol Cell Biol 20:1124–1133

Johnson AD, Kavousi M, Smith AV, Chen MH, Dehghan A, Aspelund T, Lin JP, van Duijn CM, Harris TB, Cupples LA, Uitterlinden AG, Launer L, Hofman A, Rivadeneira F, Stricker B, Yang Q, O’Donnell CJ, Gudnason V, Witteman JC (2009) Genome-wide association meta-analysis for total serum bilirubin levels. Hum Mol Genet 18:2700–2710

Johnson PR, White SA, London NJ (1996) Collagenase and human islet isolation. Cell Transplant 5:437–52

Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther 187:195–202

Jones RA, Johnson VL, Buck NR, Dobrota M, Hinton RH, Chow SC, Kass GE (1998) Fas-mediated apoptosis in mouse hepatocytes involves the processing and activation of caspases. Hepatology 27:1632–42

Jones BE, Lo CR, Liu H, Pradhan Z, Garcia L, Srinivasan A, Valentino KL, Czaja MJ (2000) Role of caspases and NF-kappaB signaling in hydrogen peroxide- and superoxide-induced hepatocyte apoptosis. Am J Physiol Gastrointest Liver Physiol 278:G693–G699

Jones HM, Houston JB (2004) Substrate depletion approach for determining in vitro metabolic clearance: time dependencies in hepatocyte and microsomal incubations. Drug Metab Dispos 32:973–982

Jones CN, Tuleuova N, Lee JY, Ramanculov E, Reddi AH, Zern MA, Revzin A (2009) Cultivating liver cells on printed arrays of hepatocyte growth factor. Biomaterials 30:3733–3741

Jorgensen L, van Beek J, Lund S, Schousboe A, Badolo L (2007) Evidence of Oatp and Mdr1 in cryopreserved rat hepatocytes. Eur J Pharm Sci 30:181–189

Josse R, Aninat C, Glaise D, Dumont J, Fessard V, Morel F, Poul JM, Guguen-Guillouzo C, Guillouzo A (2008) Long-term functional stability of human HepaRG hepatocytes and use for chronic toxicity and genotoxicity studies. Drug Metab Dispos 36:1111–1118

Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, Bouillet P, Thomas HE, Borner C, Silke J, Strasser A, Kaufmann T (2009) XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460:1035–1039

Jover R, Bort R, Gomez-Lechon MJ, Castell JV (1998) Re-expression of C/EBP alpha induces CYP2B6, CYP2C9 and CYP2D6 genes in HepG2 cells. FEBS Lett 431:227–230

Ju C, Reilly T (2012) Role of immune reactions in drug-induced liver injury (DILI). Drug Metab Rev 44:107–115

Ju C, Reilly TP, Bourdi M, Radonovich MF, Brady JN, George JW, Pohl LR (2002) Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem Res Toxicol 15:1504–1513

Judson RS, Kavlock RJ, Setzer RW, Hubal EA, Martin MT, Knudsen TB, Houck KA, Thomas RS, Wetmore BA, Dix DJ (2011) Estimating toxicity-related biological pathway altering doses for high-throughput chemical risk assessment. Chem Res Toxicol 24:451–462

Jung D, Podvinec M, Meyer UA, Mangelsdorf DJ, Fried M, Meier PJ, Kullak-Ublick GA (2002) Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. Gastroenterology 122:1954–1966

Jung D, Kullak-Ublick GA (2003) Hepatocyte nuclear factor 1 alpha: a key mediator of the effect of bile acids on gene expression. Hepatology 37:622–631

Jung D, Mangelsdorf DJ, Meyer UA (2006) Pregnane X receptor is a target of farnesoid X receptor. J Biol Chem 281:19081–19091

Jung D, Elferink MG, Stellaard F, Groothuis GM (2007) Analysis of bile acid-induced regulation of FXR target genes in human liver slices. Liver Int 27:137–144

Jungermann K, Katz N (1982) Functional hepatocellular heterogeneity. Hepatology 2:385–395

Jungermann K, Kietzmann T (1996) Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr 16:179–203

Jungermann K, Kietzmann T (1997) Role of oxygen in the zonation of carbohydrate metabolism and gene expression in liver. Kidney Int 51:402–412

Jungermann K, Kietzmann T (2000) Oxygen: modulator of metabolic zonation and disease of the liver. Hepatology 31:255–260

Kafert-Kasting S, Alexandrova K, Barthold M, Laube B, Friedrich G, Arseniev L, Hengstler JG (2006) Enzyme induction in cryopreserved human hepatocyte cultures. Toxicology 220:117–225

Kagi D, Vignaux F, Ledermann B, Burki K, Depraetere V, Nagata S, Hengartner H, Golstein P (1994) Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 265:528–530

Kakizaki S, Takizawa D, Tojima H, Horiguchi N, Yamazaki Y, Mori M (2012) Nuclear receptors CAR and PXR; therapeutic targets for cholestatic liver disease. Front Biosci 17:2988–3005

Kalaany NY, Mangelsdorf DJ (2006) LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol 68:159–191

Kalapos MP (2002) Carbamazepine-provoked hepatotoxicity and possible aetiopathological role of glutathione in the events. Retrospective review of old data and call for new investigation. Adverse Drug React Toxicol Rev 21:123–141

Kaleta C, de Figueiredo LF, Schuster S (2009) Can the whole be less than the sum of its parts? Pathway analysis in genome-scale metabolic networks using elementary flux patterns. Genome Res 19:1872–1883

Kalliokoski A, Niemi M (2009) Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 158:693–705

Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120:649–661

Kamiya A, Inoue Y, Gonzalez FJ (2003) Role of the hepatocyte nuclear factor 4alpha in control of the pregnane X receptor during fetal liver development. Hepatology 37:1375–1384

Kanamitsu S, Ito K, Sugiyama Y (2000) Quantitative prediction of in vivo drug-drug interactions from in vitro data based on physiological pharmacokinetics: use of maximum unbound concentration of inhibitor at the inlet to the liver. Pharm Res 17:336–343

Kane BJ, Zinner MJ, Yarmush ML, Toner M (2006) Liver-specific functional studies in a microfluidic array of primary mammalian hepatocytes. Anal Chem 78:4291–4298

Kanebratt KP, Andersson TB (2008) Evaluation of HepaRG cells as an in vitro model for human drug metabolism studies. Drug Metab Dispos 36:1444–1452

Kanebratt KP, Andersson TB (2008) HepaRG cells as an in vitro model for evaluation of cytochrome P450 induction in humans. Drug Metab Dispos 36:137–145

Kaneko A, Kato M, Endo C, Nakano K, Ishigai M, Takeda K (2010) Prediction of clinical CYP3A4 induction using cryopreserved human hepatocytes. Xenobiotica 40:791–799

Kang HW, Cho DW (2012) Development of an Indirect Stereolithography Technology for Scaffold Fabrication with a wide range of biomaterial selectivity. Tissue Eng Part C Methods

Kang TB, Ben-Moshe T, Varfolomeev EE, Pewzner-Jung Y, Yogev N, Jurewicz A, Waisman A, Brenner O, Haffner R, Gustafsson E, Ramakrishnan P, Lapidot T, Wallach D (2004) Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol 173:2976–2984

Kang TB, Oh GS, Scandella E, Bolinger B, Ludewig B, Kovalenko A, Wallach D (2008) Mutation of a self-processing site in caspase-8 compromises its apoptotic but not its nonapoptotic functions in bacterial artificial chromosome-transgenic mice. J Immunol 181:2522–2532

Kano A, Watanabe Y, Takeda N, Aizawa S, Akaike T (1997) Analysis of IFN-gamma-induced cell cycle arrest and cell death in hepatocytes. J Biochem 121:677–683

Kaplowitz N (2004) Drug-induced liver injury. Clin Infect Dis 38(Suppl 2):S44–8

Kaplowitz N, Deleve LD (2002) Drug-induced liver disease. Informa Healthcare, New York, USA

Karin M, Lin A (2002) NF-kappaB at the crossroads of life and death. Nat Immunol 3:221–227

Kartenbeck J, Leuschner U, Mayer R, Keppler D (1996) Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology 23:1061–1066

Kasper HU, Konze E, Kutinova Canova N, Dienes HP, Dries V (2011) Cryopreservation of precision cut tissue slices (PCTS): investigation of morphology and reactivity. Exp Toxicol Pathol 63:575–580

Kassam A, Capone JP, Rachubinski RA (2001) The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor alpha-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal beta-oxidation enzymes acyl-CoA oxidase and hydratase-dehydrogenase. Mol Cell Endocrinol 176:49–56

Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, Edwards PA (2002) Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem 277:2908–2915

Kasuya J, Sudo R, Mitaka T, Ikeda M, Tanishita K (2011) Hepatic stellate cell-mediated three-dimensional hepatocyte and endothelial cell triculture model. Tissue Eng Part A 17:361–370

Kasuya J, Sudo R, Tamogami R, Masuda G, Mitaka T, Ikeda M, Tanishita K (2012) Reconstruction of 3D stacked hepatocyte tissues using degradable, microporous poly(d, l-lactide-co-glycolide) membranes. Biomaterials 33:2693–2700

Kataropoulou M, Henderson C, Grant MH (2005) Metabolic studies of hepatocytes cultured on collagen substrata modified to contain glycosaminoglycans. Tissue Eng 11:1263–1273

Kato M, Shitara Y, Sato H, Yoshisue K, Hirano M, Ikeda T, Sugiyama Y (2008) The quantitative prediction of CYP-mediated drug interaction by physiologically based pharmacokinetic modeling. Pharm Res 25:1891–1901

Kato S, Ishii T, Hara H, Sugiura N, Kimata K, Akamatsu N (1994) Hepatocyte growth factor immobilized onto culture substrates through heparin and matrigel enhances DNA synthesis in primary rat hepatocytes. Exp Cell Res 211:53–58

Kaufmann T, Strasser A, Jost PJ (2012) Fas death receptor signalling: roles of Bid and XIAP. Cell Death Differ 19:42–50

Kawajiri K, Kobayashi Y, Ohtake F, Ikuta T, Matsushima Y, Mimura J, Pettersson S, Pollenz RS, Sakaki T, Hirokawa T, Akiyama T, Kurosumi M, Poellinger L, Kato S, Fujii-Kuriyama Y (2009) Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands. Proc Natl Acad Sci USA 106:13481–13486

Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, Fukusumi S, Habata Y, Itoh T, Shintani Y, Hinuma S, Fujisawa Y, Fujino M (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem 278:9435–9440

Kawashima S, Kobayashi K, Takama K, Higuchi T, Furihata T, Hosokawa M, Chiba K (2006) Involvement of hepatocyte nuclear factor 4alpha in the different expression level between CYP2C9 and CYP2C19 in the human liver. Drug Metab Dispos 34:1012–1018

Kehat I, Khimovich L, Caspi O, Gepstein A, Shofti R, Arbel G, Huber I, Satin J, Itskovitz-Eldor J, Gepstein L (2004) Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol 22:1282–1289

Keisu M, Andersson TB (2010) Drug-induced liver injury in humans: the case of ximelagatran. Handb Exp Pharmacol 196:407–418

Keitel V, Häussinger D (2011) TGR5 in the biliary tree. Dig Dis 29:45–7

Keitel V, Häussinger D (2012) Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenterol

Keitel V, Burdelski M, Warskulat U, Kuhlkamp T, Keppler D, Häussinger D, Kubitz R (2005) Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Hepatology 41:1160–1172

Keitel V, Reinehr R, Gatsios P, Rupprecht C, Gorg B, Selbach O, Häussinger D, Kubitz R (2007) The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 45:695–704

Keitel V, Donner M, Winandy S, Kubitz R, Häussinger D (2008a) Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 372:78–84

Keitel V, Kubitz R, Häussinger D (2008b) Endocrine and paracrine role of bile acids. World J Gastroenterol 14:5620–5629

Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Häussinger D (2009) The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 50:861–870

Keitel V, Ullmer C, Häussinger D (2010) The membrane-bound bile acid receptor TGR5 (Gpbar-1) is localized in the primary cilium of cholangiocytes. Biol Chem 391:785–789

Keller GA, West MA, Wilkes LA, Cerra FB, Simmons RL (1985) Modulation of hepatocyte protein synthesis by endotoxin-activated Kupffer cells. II. Mediation by soluble transferrable factors. Ann Surg 201:429–435

Keller GA, West MA, Harty JT, Wilkes LA, Cerra FB, Simmons RL (1985) Modulation of hepatocyte protein synthesis by endotoxin-activated Kupffer cells. III. Evidence for the role of a monokine similar to but not identical with interleukin-1. Ann Surg 201:436–443

Keller GA, West MA, Cerra FB, Simmons RL (1985) Multiple systems organ failure. Modulation of hepatocyte protein synthesis by endotoxin activated Kupffer cells. Ann Surg 201:87–95

Keller GA, West MA, Cerra FB, Simmons RL (1986) Macrophage-mediated modulation of hepatocyte protein synthesis. Effect of dexamethasone. Arch Surg 121:1199–1205

Kelley SK, Nilsson CB, Green MH, Green JB, Hakansson H (2000) Mobilization of vitamin A stores in rats after administration of 2,3, 7,8-tetrachlorodibenzo-p-dioxin: a kinetic analysis. Toxicol Sci 55:478–484

Kelm JM, Timmins NE, Brown CJ, Fussenegger M, Nielsen LK (2003) Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types. Biotechnol Bioeng 83:173–180

Kelm JM, Fussenegger M (2004) Microscale tissue engineering using gravity-enforced cell assembly. Trends Biotechnol 22:195–202

Kelm JM, Djonov V, Ittner LM, Fluri D, Born W, Hoerstrup SP, Fussenegger M (2006) Design of custom-shaped vascularized tissues using microtissue spheroids as minimal building units. Tissue Eng 12:2151–2160

Keppler D (2011) Multidrug resistance proteins (MRPs, ABCCs): importance for pathophysiology and drug therapy. Handb Exp Pharmacol 299–323

Kern A, Bader A, Pichlmayr R, Sewing KF (1997) Drug metabolism in hepatocyte sandwich cultures of rats and humans. Biochem Pharmacol 54:761–772

Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

Khan AA, Chow EC, Porte RJ, Pang KS, Groothuis GM (2009) Expression and regulation of the bile acid transporter, OSTalpha-OSTbeta in rat and human intestine and liver. Biopharm Drug Dispos 30:241–258

Khan AA, Chow EC, Van Loenen-Weemaes AM, Porte RJ, Pang KS, Groothuis GM (2009) Comparison of effects of VDR versus PXR, FXR and GR ligands on the regulation of CYP3A isozymes in rat and human intestine and liver. Eur J Pharm Sci 37:115–125

Khan MA, Ellis R, Inman MD, Bates JH, Sanderson MJ, Janssen LJ (2010) Influence of airway wall stiffness and parenchymal tethering on the dynamics of bronchoconstriction. Am J Physiol Lung Cell Mol Physiol 299:L98–L108

Khan AA, Dragt BS, Porte RJ, Groothuis GM (2010) Regulation of VDR expression in rat and human intestine and liver–consequences for CYP3A expression. Toxicol In Vitro 24:822–829

Khan AA, Chow EC, Porte RJ, Pang KS, Groothuis GM (2011) The role of lithocholic acid in the regulation of bile acid detoxication, synthesis, and transport proteins in rat and human intestine and liver slices. Toxicol In Vitro 25:80–90

Khetani SR, Bhatia SN (2008) Microscale culture of human liver cells for drug development. Nat Biotechnol 26:120–126

Khor TO, Ibrahim S, Kong AN (2006) Toxicogenomics in drug discovery and drug development: potential applications and future challenges. Pharm Res 23:1659–1664

Khuu DN, Najimi M, Sokal EM (2007) Epithelial cells with hepatobiliary phenotype: is it another stem cell candidate for healthy adult human liver? World J Gastroenterol 13:1554–1560

Kienhuis AS, van de Poll MC, Wortelboer H, van Herwijnen M, Gottschalk R, Dejong CH, Boorsma A, Paules RS, Kleinjans JC, Stierum RH, van Delft JH (2009) Parallelogram approach using rat-human in vitro and rat in vivo toxicogenomics predicts acetaminophen-induced hepatotoxicity in humans. Toxicol Sci 107:544–552

Kienhuis AS, Wortelboer HM, Maas WJ, van Herwijnen M, Kleinjans JC, van Delft JH, Stierum RH (2007) A sandwich-cultured rat hepatocyte system with increased metabolic competence evaluated by gene expression profiling. Toxicol In Vitro 21:892–901

Kietzmann T, Dimova EY, Flugel D, Scharf JG (2006) Oxygen: modulator of physiological and pathophysiological processes in the liver. Z Gastroenterol 44:67–76

Kietzmann T, Jungermann K (1997) Modulation by oxygen of zonal gene expression in liver studied in primary rat hepatocyte cultures. Cell Biol Toxicol 13:243–55

Kim JS, Southard JH (1999) Membrane stabilizing effects of calcium and taxol during the cold storage of isolated rat hepatocytes. Transplantation 68:938–943

Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N, Lee SH, Nguyen J, Sanchez-Pernaute R, Bankiewicz K, McKay R (2002) Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 418:50–56

Kim MS, Shigenaga J, Moser A, Feingold K, Grunfeld C (2003) Repression of farnesoid X receptor during the acute phase response. J Biol Chem 278:8988–8995

Kim SH, Hoshiba T, Akaike T (2003) Effect of carbohydrates attached to polystyrene on hepatocyte morphology on sugar-derivatized polystyrene matrices. J Biomed Mater Res A 67:1351–1359

Kim JY, Ahn MR, Kim DK, Sheen YY (2004) Histone deacetylase inhibitor stimulate CYP3A4 proximal promoter activity in HepG2 cells. Arch Pharm Res 27:407–414

Kim I, Morimura K, Shah Y, Yang Q, Ward JM, Gonzalez FJ (2007) Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28:940–946

Kim D, Rath O, Kolch W, Cho KH (2007) A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK pathways. Oncogene 26:4571–4579

Kim S, Dere E, Burgoon LD, Chang CC, Zacharewski TR (2009) Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci 112:229–244

Kim M, Lee JY, Jones CN, Revzin A, Tae G (2010) Heparin-based hydrogel as a matrix for encapsulation and cultivation of primary hepatocytes. Biomaterials 31:3596–3603

Kim Y, Lasher CD, Milford LM, Murali TM, Rajagopalan P (2010) A comparative study of genome-wide transcriptional profiles of primary hepatocytes in collagen sandwich and monolayer cultures. Tissue Eng Part C Methods 16:1449–1460

Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, Kim J, Aryee MJ, Ji H, Ehrlich LI, Yabuuchi A, Takeuchi A, Cunniff KC, Hongguang H, McKinney-Freeman S, Naveiras O, Yoon TJ, Irizarry RA, Jung N, Seita J, Hanna J, Murakami P, Jaenisch R, Weissleder R, Orkin SH, Weissman IL, Feinberg AP, Daley GQ (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467:285–290

Kim BS, Park IK, Hoshiba T, Jiang HL, Choi YJ, Akaike T, Cho CS (2011) Design of artificial extracellular matrices for tissue engineering. Prog Polym Sci 36:238–268

Kimata T, Nagaki M, Tsukada Y, Ogiso T, Moriwaki H (2006) Hepatocyte nuclear factor-4alpha and -1 small interfering RNA inhibits hepatocyte differentiation induced by extracellular matrix. Hepatol Res 35:3–9

Kin T, Johnson PR, Shapiro AM, Lakey JR (2007) Factors influencing the collagenase digestion phase of human islet isolation. Transplantation 83:7–12

Kindmark A, Jawaid A, Harbron CG, Barratt BJ, Bengtsson OF, Andersson TB, Carlsson S, Cederbrant KE, Gibson NJ, Armstrong M, Lagerstrom-Fermer ME, Dellsen A, Brown EM, Thornton M, Dukes C, Jenkins SC, Firth MA, Harrod GO, Pinel TH, Billing-Clason SM, Cardon LR, March RE (2008) Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 8:186–195

Kipp H, Arias IM (2002) Trafficking of canalicular ABC transporters in hepatocytes. Annu Rev Physiol 64:595–608

Kirovski G, Gabele E, Dorn C, Moleda L, Niessen C, Weiss TS, Wobser H, Schacherer D, Buechler C, Wasmuth HE, Hellerbrand C (2010) Hepatic steatosis causes induction of the chemokine RANTES in the absence of significant hepatic inflammation. Int J Clin Exp Pathol 3:675–680

Kis E, Ioja E, Nagy T, Szente L, Heredi-Szabo K, Krajcsi P (2009) Effect of membrane cholesterol on BSEP/Bsep activity: species specificity studies for substrates and inhibitors. Drug Metab Dispos 37:1878–1886

Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. Embo J 14:5579–5588

Kitani H, Takenouchi T, Sato M, Yoshioka M, Yamanaka N (2010) A novel isolation method for macrophage-like cells from mixed primary cultures of adult rat liver cells. J Immunol Methods 360:47–55

Klamt S (2006) Generalized concept of minimal cut sets in biochemical networks. Biosystems 83:233–47

Klamt S, Gilles ED (2004) Minimal cut sets in biochemical reaction networks. Bioinformatics 20:226–234

Klassen LW, Thiele GM, Duryee MJ, Schaffert CS, Deveney AL, Hunter CD, Olinga P, Tuma DJ (2008) An in vitro method of alcoholic liver injury using precision-cut liver slices from rats. Biochem Pharmacol 76:426–436

Kleinfeld AM, Prothro D, Brown DL, Davis RC, Richieri GV, Demaria A (1996) Increases in serum unbound free fatty acid levels following coronary angioplasty. Am J Cardiol 78:1350–1354

Kleinman HK, McGarvey ML, Hassell JR, Star VL, Cannon FB, Laurie GW, Martin GR (1986) Basement membrane complexes with biological activity. Biochemistry 25:312–318

Kline ER, Bassit L, Hernandez-Santiago BI, Detorio MA, Liang B, Kleinhenz DJ, Walp ER, Dikalov S, Jones DP, Schinazi RF, Sutliff RL (2009) Long-term exposure to AZT, but not d4T, increases endothelial cell oxidative stress and mitochondrial dysfunction. Cardiovasc Toxicol 9:1–12

Klingmuller U, Bauer A, Bohl S, Nickel PJ, Breitkopf K, Dooley S, Zellmer S, Kern C, Merfort I, Sparna T, Donauer J, Walz G, Geyer M, Kreutz C, Hermes M, Gotschel F, Hecht A, Walter D, Egger L, Neubert K, Borner C, Brulport M, Schormann W, Sauer C, Baumann F, Preiss R, Macnelly S, Godoy P, Wiercinska E, Ciuclan L, Edelmann J, Zeilinger K, Heinrich M, Zanger UM, Gebhardt R, Maiwald T, Heinrich R, Timmer J, von Weizsacker F, Hengstler JG (2006) Primary mouse hepatocytes for systems biology approaches: a standardized in vitro system for modelling of signal transduction pathways. Syst Biol (Stevenage) 153:433–447

Kmiec Z (2001) Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol 161:III–XIII, 1–151

Knerr S, Schrenk D (2006) Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in experimental models. Mol Nutr Food Res 50:897–907

Knight TR, Jaeschke H (2004) (2004) Peroxynitrite formation and sinusoidal endothelial cell injury during acetaminophen-induced hepatotoxicity in mice. Comp Hepatol 3(1):S46

Knight TR, Fariss MW, Farhood A, Jaeschke H (2003) Role of lipid peroxidation as a mechanism of liver injury after acetaminophen overdose in mice. Toxicol Sci 76:229–236

Knight E, Murray B, Carnachan R, Przyborski S (2011) Alvetex(R): polystyrene scaffold technology for routine three dimensional cell culture. Methods Mol Biol 695:323–340

Knobeloch D, Ehnert S, Schyschka L, Buchler P, Schoenberg M, Kleeff J, Thasler WE, Nussler NC, Godoy P, Hengstler J, Nussler AK (2012) Human hepatocytes: isolation, culture, and quality procedures. Methods Mol Biol 806:99–120

Kobayashi N, Noguchi H, Westerman KA, Watanabe T, Matsumura T, Totsugawa T, Fujiwara T, Leboulch P, Tanaka N (2001) Cre/loxP-based reversible immortalization of human hepatocytes. Cell Transpl 10(4–5):383–386

Koebe HG, Dahnhardt C, Muller-Hocker J, Wagner H, Schildberg FW (1996) Cryopreservation of porcine hepatocyte cultures. Cryobiology 33:127–141

Koebe HG, Dunn JC, Toner M, Sterling LM, Hubel A, Cravalho EG, Yarmush ML, Tompkins RG (1990) A new approach to the cryopreservation of hepatocytes in a sandwich culture configuration. Cryobiology 27:576–584

Koebe HG, Muhling B, Deglmann CJ, Schildberg FW (1999) Cryopreserved porcine hepatocyte cultures. Chem Biol Interact 121:99–115

Koebe HG, Pahernik S, Eyer P, Schildberg FW (1994) Collagen gel immobilization: a useful cell culture technique for long-term metabolic studies on human hepatocytes. Xenobiotica 24:95–107

Koepsell H, Endou H (2004) The SLC22 drug transporter family. Pflugers Arch 447:666–676

Koepsell H, Lips K, Volk C (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227–1251

Kohle C, Bock KW (2006) Activation of coupled Ah receptor and Nrf2 gene batteries by dietary phytochemicals in relation to chemoprevention. Biochem Pharmacol 72:795–805

Kohn MC, Sewall CH, Lucier GW, Portier CJ (1996) A mechanistic model of effects of dioxin on thyroid hormones in the rat. Toxicol Appl Pharmacol 136:29–48

Koide N, Shinji T, Tanabe T, Asano K, Kawaguchi M, Sakaguchi K, Koide Y, Mori M, Tsuji T (1989) Continued high albumin production by multicellular spheroids of adult rat hepatocytes formed in the presence of liver-derived proteoglycans. Biochem Biophys Res Commun 161:385–391

Koike M, Matsushita M, Taguchi K, Uchino J (1996) Function of culturing monolayer hepatocytes by collagen gel coating and coculture with nonparenchymal cells. Artif Organs 20:186–192

Koike C, Moore R, Negishi M (2007) Extracellular signal-regulated kinase is an endogenous signal retaining the nuclear constitutive active/androstane receptor (CAR) in the cytoplasm of mouse primary hepatocytes. Mol Pharmacol 71(5):1217–1221

Koide N, Morikawa A, Naiki Y, Tumurkhuu G, Yoshida T, Ikeda H, Yokochi T (2009) Low susceptibility of NC/Nga mice to tumor necrosis factor-alpha-mediated lethality and hepatocellular damage with D-galactosamine sensitization. Clin Immunol 130:225–232

Koide T, Pang WL, Baliga NS (2009) The role of predictive modelling in rationally re-engineering biological systems. Nat Rev Microbiol 7:297–305

Koizumi T, Aoki T, Kobayashi Y, Yasuda D, Izumida Y, Jin Z, Nishino N, Shimizu Y, Kato H, Murai N, Niiya T, Enami Y, Mitamura K, Yamamoto T, Kusano M (2007) Long-term maintenance of the drug transport activity in cryopreservation of microencapsulated rat hepatocytes. Cell Transpl 16:67–73

Kojima R, Yoshimoto K, Takahashi E, Ichino M, Miyoshi H, Nagasaki Y (2009) Spheroid array of fetal mouse liver cells constructed on a PEG-gel micropatterned surface: upregulation of hepatic functions by co-culture with nonparenchymal liver cells. Lab Chip 9(14):1991–1993

Kolios G, Valatas V, Kouroumalis E (2006) Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol 12:7413–7420

Komura H, Kawase A, Iwaki M (2005) Application of substrate depletion assay for early prediction of nonlinear pharmacokinetics in drug discovery: assessment of nonlinearity of metoprolol, timolol, and propranolol. J Pharm Sci 94:2656–2666

Kon K, Kim JS, Jaeschke H, Lemasters JJ (2004) Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology 40:1170–1179

Kon K, Kim JS, Uchiyama A, Jaeschke H, Lemasters JJ (2010) Lysosomal iron mobilization and induction of the mitochondrial permeability transition in acetaminophen-induced toxicity to mouse hepatocytes. Toxicol Sci 117:101–108

Konig J, Nies AT, Cui Y, Leier I, Keppler D (1999) Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta 1461:377–394

Konig J, Cui Y, Nies AT, Keppler D (2000) A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol 278:G156–G164

Konig J, Cui Y, Nies AT, Keppler D (2000) Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem 275:23161–23168

Konig J, Seithel A, Gradhand U, Fromm MF (2006) Pharmacogenomics of human OATP transporters. Naunyn Schmiedebergs Arch Pharmacol 372:432–443

Konig J (2011) Uptake transporters of the human OATP family: molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms. Handb Exp Pharmacol 1–28

Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8:279–289

Kool M, de Haas M, Scheffer GL, Scheper RJ, van Eijk MJ, Juijn JA, Baas F, Borst P (1997) Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res 57:3537–3547

Kordes C, Häussinger D (2013) Hepatic stem cell niches. J Clin Invest 23:1874–1880

Kordes C, Sawitza I, Häussinger D (2008) Canonical Wnt signaling maintains the quiescent stage of hepatic stellate cells. Biochem Biophys Res Commun 367:116–123

Kordes C, Sawitza I, Häussinger D (2009) Hepatic and pancreatic stellate cells in focus. Biol Chem 390:1003–1012

Kordes C, Sawitza I, Muller-Marbach A, Ale-Agha N, Keitel V, Klonowski-Stumpe H, Häussinger D (2007) CD133 + hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 352:410–417

Kordes C, Sawitza I, Götze S, Häussinger D (2012) Stellate cells from rat pancreas are stem cells and can contribute to liver regeneration. PLoS One 7:e51878

Kordes C, Sawitza I, Götze S, Häussinger D (2013) Hepatic stellate cells support hematopoiesis and are liver-resident mesenchymal stem cells. Cell Physiol Biochem 31:290–304

Korita PV, Wakai T, Shirai Y, Matsuda Y, Sakata J, Takamura M, Yano M, Sanpei A, Aoyagi Y, Hatakeyama K, Ajioka Y (2010) Multidrug resistance-associated protein 2 determines the efficacy of cisplatin in patients with hepatocellular carcinoma. Oncol Rep 23:965–972

Korpal M, Lee ES, Hu G, Kang Y (2008) The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 283:14910–14914

Kost DP, Michalopoulos GK (1991) Effect of 2% dimethyl sulfoxide on the mitogenic properties of epidermal growth factor and hepatocyte growth factor in primary hepatocyte culture. J Cell Physiol 147:274–280

Kostrubsky VE, Sinclair JF, Ramachandran V, Venkataramanan R, Wen YH, Kindt E, Galchev V, Rose K, Sinz M, Strom SC (2000) The role of conjugation in hepatotoxicity of troglitazone in human and porcine hepatocyte cultures. Drug Metab Dispos 28:1192–1197

Kotani N, Maeda K, Watanabe T, Hiramatsu M, Gong LK, Bi YA, Takezawa T, Kusuhara H, Sugiyama Y (2011) Culture period-dependent changes in the uptake of transporter substrates in sandwich-cultured rat and human hepatocytes. Drug Metab Dispos 39:1503–1510

Krahenbuhl S, Talos C, Fischer S, Reichen J (1994) Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology 19:471–479

Kramer W, Stengelin S, Baringhaus KH, Enhsen A, Heuer H, Becker W, Corsiero D, Girbig F, Noll R, Weyland C (1999) Substrate specificity of the ileal and the hepatic Na(+)/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters. J Lipid Res 40:1604–1617

Krebs HA (1933) Untersuchungen über den Stoffwechsel der Aminosäuren im Tierkörper. Hoppe-Seyl Z 217:190

Kristensen LS, Nielsen HM, Hansen LL (2009) Epigenetics and cancer treatment. Eur J Pharmacol 625:131–142

Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134:657–667

Kruithof-de Julio M, Labruyere WT, Ruijter JM, Vermeulen JL, Stanulovic V, Stallen JM, Baldysiak-Figiel A, Gebhardt R, Lamers WH, Hakvoort TB (2005) The RL-ET-14 cell line mediates expression of glutamine synthetase through the upstream enhancer/promoter region. J Hepatol 43:126–131

Krumdieck CL, dos Santos JE, Ho KJ (1980) A new instrument for the rapid preparation of tissue slices. Anal Biochem 104:118–23

Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M (2005) Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438:685–689

Küblbeck J, Reinisalo M, Mustonen R, Honkakoski P (2010) Up-regulation of CYP expression in hepatoma cells stably transfected by chimeric nuclear receptors. Eur J Pharm Sci 40(4):263–272

Kuiper J, Brouwer A, Knook DL, van Berkel TJC (1994) Kupffer and sinusoidal endothelial cells. In: Arias IM, Boyer JL, Fausto N, Jacoby WB, Schachler DA, Shafritz DA (eds) The liver: biology and pathobiology, 3rd edn. Raven Press, New York, pp 791–818

Kullak-Ublick GA, Glasa J, Boker C, Oswald M, Grutzner U, Hagenbuch B, Stieger B, Meier PJ, Beuers U, Kramer W, Wess G, Paumgartner G (1997) Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas. Gastroenterology 113:1295–1305

Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, Hagenbuch B (2001) Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 120:525–533

Kullak-Ublick GA, Stieger B, Hagenbuch B, Meier PJ (2000) Hepatic transport of bile salts. Semin Liver Dis 20:273–292

Kullak-Ublick GA, Stieger B, Meier PJ (2004) Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 126:322–342

Kuo FC, Darnell JE Jr (1991) Evidence that interaction of hepatocytes with the collecting (hepatic) veins triggers position-specific transcription of the glutamine synthetase and ornithine aminotransferase genes in the mouse liver. Mol Cell Biol 11:6050–6058

Kurose I, Miura S, Higuchi H, Watanabe N, Kamegaya Y, Takaishi M, Tomita K, Fukumura D, Kato S, Ishii H (1996) Increased nitric oxide synthase activity as a cause of mitochondrial dysfunction in rat hepatocytes: roles for tumor necrosis factor alpha. Hepatology 24:1185–1192

Kusano T, Aoki T, Yasuda D, Matsumoto S, Jin Z, Nishino N, Hayashi K, Odaira M, Yamada K, Koizumi T, Izumida Y, Mitamura K, Enami Y, Niiya T, Murai N, Kato H, Shimizu Y, Kou K, Furukawa Y, Matsusita M, Todo S, Shioda S, Kusano M (2008) Microencapsule technique protects hepatocytes from cryoinjury. Hepatol Res 38:593–600

Kusuhara H, Sugiyama Y (2009) In vitro-in vivo extrapolation of transporter-mediated clearance in the liver and kidney. Drug Metab Pharmacokinet 24:37–52

Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T (2001) Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410:116–120

Lacour S, Gautier JC, Pallardy M, Roberts R (2005) Cytokines as potential biomarkers of liver toxicity. Cancer Biomark 1:29–39

Lacronique V, Mignon A, Fabre M, Viollet B, Rouquet N, Molina T, Porteu A, Henrion A, Bouscary D, Varlet P, Joulin V, Kahn A (1996) Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice. Nat Med 2:80–86

Lagaye S, Shen H, Saunier B, Nascimbeni M, Gaston J, Bourdoncle P, Hannoun L, Massault, PP, Vallet-Pichard A, Mallet V, Pol S (2012) Efficient replication of primary or culture hepatitis C virus isolates in human liver slices: a relevant ex vivo model of liver infection. Hepatology

Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T (2002) Identification of tissue-specific microRNAs from mouse. Curr Biol 12:735–739

Lahoz A, Donato MT, Montero S, Castell JV, Gomez-Lechon MJ (2008) A new in vitro approach for the simultaneous determination of phase I and phase II enzymatic activities of human hepatocyte preparations. Rapid Commun Mass Spectrom 22:240–244

Laine JE, Auriola S, Pasanen M, Juvonen RO (2009) Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica 39:11–21

Lake BG, Price RJ, Giddings AM, Walters DG (2009) In vitro assays for induction of drug metabolism. Methods Mol Biol 481:47–58

Lako M, Lindsay S, Lincoln J, Cairns PM, Armstrong L, Hole N (2001) Characterisation of Wnt gene expression during the differentiation of murine embryonic stem cells in vitro: role of Wnt3 in enhancing haematopoietic differentiation. Mech Dev 103:49–59

Lam JL, Benet LZ (2004) Hepatic microsome studies are insufficient to characterize in vivo hepatic metabolic clearance and metabolic drug-drug interactions: studies of digoxin metabolism in primary rat hepatocytes versus microsomes. Drug Metab Dispos 32:1311–1316

Lam P, Wang R, Ling V (2005) Bile acid transport in sister of P-glycoprotein (ABCB11) knockout mice. Biochemistry 44:12598–605

Lamba JK, Lamba V, Yasuda K, Lin YS, Assem M, Thompson E, Strom S, Schuetz E (2004) Expression of constitutive androstane receptor splice variants in human tissues and their functional consequences. J Pharmacol Exp Ther 311:811–821

Lamba J, Lamba V, Strom S, Venkataramanan R, Schuetz E (2008) Novel single nucleotide polymorphisms in the promoter and intron 1 of human pregnane X receptor/NR1I2 and their association with CYP3A4 expression. Drug Metab Dispos 36:169–181

Lambert G, Amar MJ, Guo G, Brewer HB Jr, Gonzalez FJ, Sinal CJ (2003) The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem 278:2563–2570

Lambert CB, Spire C, Renaud MP, Claude N, Guillouzo A (2009) Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro 23:466–475

Lamers W, Moorman A, Charles R (1989) The metabolic lobulus, a key to the architecture of the liver. In: Revisiones Sobre Biologia Celular, Springer, New York

Lammert C, Bjornsson E, Niklasson A, Chalasani N (2010) Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology 51:615–620

Landrier JF, Eloranta JJ, Vavricka SR, Kullak-Ublick GA (2006) The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes. Am J Physiol Gastrointest Liver Physiol 290:G476–G485

Landry J, Bernier D, Ouellet C, Goyette R, Marceau N (1985) Spheroidal aggregate culture of rat liver cells: histotypic reorganization, biomatrix deposition, and maintenance of functional activities. J Cell Biol 101:914–923

Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, Kauppinen S, Orum H (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327:198–201

Lang R, Stern MM, Smith L, Liu Y, Bharadwaj S, Liu G, Baptista PM, Bergman CR, Soker S, Yoo JJ, Atala A, Zhang Y (2011) Three-dimensional culture of hepatocytes on porcine liver tissue-derived extracellular matrix. Biomaterials 32:7042–7052

Langenbach R, Malick L, Tompa A, Kuszynski C, Freed H, Huberman E (1979) Maintenance of adult rat hepatocytes on C3H/10T1/2 cells. Cancer Res 39:3509–3514

Laskin DL, Pilaro AM, Ji S (1986) Potential role of activated macrophages in acetaminophen hepatotoxicity. II. Mechanism of macrophage accumulation and activation. Toxicol Appl Pharmacol 86:216–226

Laskin DL, Gardner CR, Price VF, Jollow DJ (1995) Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 21:1045–1050

Lave T, Parrott N, Grimm HP, Fleury A, Reddy M (2007) Challenges and opportunities with modelling and simulation in drug discovery and drug development. Xenobiotica 37:1295–1310

le Vee M, Jouan E, Fardel O (2010) Involvement of aryl hydrocarbon receptor in basal and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced expression of target genes in primary human hepatocytes. Toxicol In Vitro 24:1775–1781

Lecluyse EL (2001) Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. Eur J Pharm Sci 13:343–368

Lecluyse EL, Audus KL, Hochman JH (1994) Formation of extensive canalicular networks by rat hepatocytes cultured in collagen-sandwich configuration. Am J Physiol 266:C1764–C1774

Lecluyse EL, Bullock PL, Parkinson A, Hochman JH (1996) Cultured rat hepatocytes. Pharm Biotechnol 8:121–159

Ledwith BJ, Johnson TE, Wagner LK, Pauley CJ, Manam S, Galloway SM, Nichols WW (1996) Growth regulation by peroxisome proliferators: opposing activities in early and late G1. Cancer Res 56:3257–3264

Lee HK, Lewis LD (2011) Pharmacogenetics of flucloxacillin and amoxicillin-clavulanate associated hepatic dysfunction/injury. In: Wu AHB, Yeo KTJ (eds) Pharmacogenomic testing in current clinical practice. implementation in the clinical laboratory, pp 239–247

Lee CH, Bradley G, Zhang JT, Ling V (1993) Differential expression of P-glycoprotein genes in primary rat hepatocyte culture. J Cell Physiol 157:392–402

Lee HK, Lee YK, Park SH, Kim YS, Park SH, Lee JW, Kwon HB, Soh J, Moore DD, Choi HS (1998) Structure and expression of the orphan nuclear receptor SHP gene. J Biol Chem 273:14398–14402

Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD (2000) The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression. Mol Cell Biol 20:187–195

Lee WM (2003) Drug-induced hepatotoxicity. N Engl J Med 349:474–485

Lee CM, Yeoh GC, Olynyk JK (2004) Differential effects of gadolinium chloride on Kupffer cells in vivo and in vitro. Int J Biochem Cell Biol 36:481–488

Lee W, Glaeser H, Smith LH, Roberts RL, Moeckel GW, Gervasini G, Leake BF, Kim RB (2005) Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J Biol Chem 280:9610–9617

Lee PJ, Hung PJ, Lee LP (2007) An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture. Biotechnol Bioeng 97:1340–1346

Lee J, Padhye A, Sharma A, Song G, Miao J, Mo YY, Wang L, Kemper JK (2010) A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. J Biol Chem 285:12604–12611

Lee CG, Kim YW, Kim EH, Meng Z, Huang W, Hwang SJ, Kim SG (2012) Farnesoid X receptor protects hepatocytes from injury by repressing miR-199a-3p, which increases levels of LKB1. Gastroenterology 142(1206–1217):e7

Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89:147–191

Lefebvre P, Chinetti G, Fruchart JC, Staels B (2006) Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 116:571–580

Lelbach A, Scharf JG, Ramadori G (2001) Regulation of insulin-like growth factor-I and of insulin-like growth factor binding protein-1, -3 and -4 in cocultures of rat hepatocytes and Kupffer cells by interleukin-6. J Hepatol 35:558–567

Lemaire B, Beck M, Jaspart M, Debier C, Calderon PB, Thome JP, Rees JF (2011) Precision-Cut Liver Slices of Salmo salar as a tool to investigate the oxidative impact of CYP1A-mediated PCB 126 and 3-methylcholanthrene metabolism. Toxicol In Vitro 25:335–342

Lerche-Langrand C, Toutain HJ (2000) Precision-cut liver slices: characteristics and use for in vitro pharmaco-toxicology. Toxicology 153:221–253

Leu JI, Crissey MA, Craig LE, Taub R (2003) Impaired hepatocyte DNA synthetic response posthepatectomy in insulin-like growth factor binding protein 1-deficient mice with defects in C/EBP beta and mitogen-activated protein kinase/extracellular signal-regulated kinase regulation. Mol Cell Biol 23:1251–1259

Leuthold S, Hagenbuch B, Mohebbi N, Wagner CA, Meier PJ, Stieger B (2009) Mechanisms of pH-gradient driven transport mediated by organic anion polypeptide transporters. Am J Physiol Cell Physiol 296:C570–C582

Leverrier Y, Ridley AJ (2001) Apoptosis: caspases orchestrate the ROCK ‘n’ bleb. Nat Cell Biol 3:E91–E93

Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20

Li T, Chiang JY (2005) Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription. Am J Physiol Gastrointest Liver Physiol 288:G74–G84

Li AP, Colburn SM, Beck DJ (1992) A simplified method for the culturing of primary adult rat and human hepatocytes as multicellular spheroids. In Vitro Cell Dev Biol 28A:673–677

Li Q, Kay MA, Finegold M, Stratford-Perricaudet LD, Woo SL (1993) Assessment of recombinant adenoviral vectors for hepatic gene therapy. Hum Gene Ther 4:403–409

Li AP, Maurel P, Gomez-Lechon MJ, Cheng LC, Jurima-Romet M (1997) Preclinical evaluation of drug-drug interaction potential: present status of the application of primary human hepatocytes in the evaluation of cytochrome P450 induction. Chem Biol Interact 107:5–16

Li L, Lee TK, Meier PJ, Ballatori N (1998) Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter. J Biol Chem 273:16184–16191

Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501

Li AP, Gorycki PD, Hengstler JG, Kedderis GL, Koebe HG, Rahmani R, de Sousas G, Silva JM, Skett P (1999) Present status of the application of cryopreserved hepatocytes in the evaluation of xenobiotics: consensus of an international expert panel. Chem Biol Interact 121:117–123

Li L, Meier PJ, Ballatori N (2000) Oatp2 mediates bidirectional organic solute transport: a role for intracellular glutathione. Mol Pharmacol 58:335–40

Li N, Hartley DP, Cherrington NJ, Klaassen CD (2002) Tissue expression, ontogeny, and inducibility of rat organic anion transporting polypeptide 4. J Pharmacol Exp Ther 301:551–560

Li J, Kaneko T, Wang Y, Qin LQ, Wang PY, Sato A (2002) Troglitazone enhances the hepatotoxicity of acetaminophen by inducing CYP3A in rats. Toxicology 176:91–100

Li S, Sanna S, Maschio A, Busonero F, Usala G, Mulas A, Lai S, Dei M, Orru M, Albai G, Bandinelli S, Schlessinger D, Lakatta E, Scuteri A, Najjar SS, Guralnik J, Naitza S, Crisponi L, Cao A, Abecasis G, Ferrucci L, Uda M, Chen WM, Nagaraja R (2007) The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet 3:e194

Li M, Yuan H, Li N, Song G, Zheng Y, Baratta M, Hua F, Thurston A, Wang J, Lai Y (2008) Identification of interspecies difference in efflux transporters of hepatocytes from dog, rat, monkey and human. Eur J Pharm Sci 35:114–26

Li N, Bi YA, Duignan DB, Lai Y (2009a) Quantitative expression profile of hepatobiliary transporters in sandwich cultured rat and human hepatocytes. Mol Pharm 6:1180–1189

Li L, Jick H, Jick SS (2009b) Updated study on risk of cholestatic liver disease and flucloxacillin. Br J Clin Pharmacol 68:269–270

Li R, Oteiza A, Sorensen KK, McCourt P, Olsen R, Smedsrod B, Svistounov D (2011) Role of liver sinusoidal endothelial cells and stabilins in elimination of oxidized low-density lipoproteins. Am J Physiol Gastrointest Liver Physiol 300:G71–G81

Liang D, Hagenbuch B, Stieger B, Meier PJ (1993) Parallel decrease of Na(+)-taurocholate cotransport and its encoding mRNA in primary cultures of rat hepatocytes. Hepatology 18:1162–1166

Liao W, Ning G (2006) Knockdown of apolipoprotein B, an atherogenic apolipoprotein, in HepG2 cells by lentivirus-mediated siRNA. Biochem Biophys Res Commun 344:478–483

Liao X, Wang Y, Wong CW (2010) Troglitazone induces cytotoxicity in part by promoting the degradation of peroxisome proliferator-activated receptor gamma co-activator-1alpha protein. Br J Pharmacol 161:771–781

Liedtke C, Trautwein C (2011) The role of TNF and Fas dependent signaling in animal models of inflammatory liver injury and liver cancer. Eur J Cell Biol 91:582–589

Lillegard JB, Fisher JE, Nedredal G, Luebke-Wheeler J, Bao J, Wang W, Amoit B, Nyberg SL (2011) Normal atmospheric oxygen tension and the use of antioxidants improve hepatocyte spheroid viability and function. J Cell Physiol 226:2987–2996

Lim PL, Liu J, Go ML, Boelsterli UA (2008) The mitochondrial superoxide/thioredoxin-2/Ask1 signaling pathway is critically involved in troglitazone-induced cell injury to human hepatocytes. Toxicol Sci 101:341–349

Limmer A, Knolle PA (2001) Liver sinusoidal endothelial cells: a new type of organ-resident antigen-presenting cell. Arch Immunol Ther Exp (Warsz) 49(Suppl 1):S7–S11

Lin KH, Hino H, Maeda S, Inagaki H, Airat JV, Saito T (1995) Albumin synthesis by rat hepatocytes cultured on collagen gels is sustained specifically by heparin. Exp Cell Res 219:717–721

Lin RZ, Chang HY (2008) Recent advances in three-dimensional multicellular spheroid culture for biomedical research. Biotechnol J 3:1172–1184

Lindros KO, Penttila KE (1985) Digitonin-collagenase perfusion for efficient separation of periportal or perivenous hepatocytes. Biochem J 228:757–760

Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R (2008) SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med 359:789–799

Lipniacki T, Paszek P, Brasier AR, Luxon B, Kimmel M (2004) Mathematical model of NF-kappaB regulatory module. J Theor Biol 228:195–215

Lippincott JB (1993) Diseases of the liver. Wiley-Blackwell, Philadelphia

Liu X, Brouwer KL, Gan LS, Brouwer KR, Stieger B, Meier PJ, Audus KL, Lecluyse EL (1998) Partial maintenance of taurocholate uptake by adult rat hepatocytes cultured in a collagen sandwich configuration. Pharm Res 15:1533–9

Liu X, Lecluyse EL, Brouwer KR, Gan LS, Lemasters JJ, Stieger B, Meier PJ, Brouwer KL (1999) Biliary excretion in primary rat hepatocytes cultured in a collagen-sandwich configuration. Am J Physiol 277:G12–G21

Liu ZX, Govindarajan S, Kaplowitz N (2004) Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology 127:1760–1774

Liu ZX, Han D, Gunawan B, Kaplowitz N (2006) Neutrophil depletion protects against murine acetaminophen hepatotoxicity. Hepatology 43:1220–1230

Liu H, Zheng F, Cao Q, Ren B, Zhu L, Striker G, Vlassara H (2006) Amelioration of oxidant stress by the defensin lysozyme. Am J Physiol Endocrinol Metab 290:E824–E832

Liu J, Abate W, Xu J, Corry D, Kaul B, Jackson SK (2011) Three-dimensional spheroid cultures of A549 and HepG2 cells exhibit different lipopolysaccharide (LPS) receptor expression and LPS-induced cytokine response compared with monolayer cultures. Innate Immun 17:245–255

Llambi F, Moldoveanu T, Tait SW, Bouchier-Hayes L, Temirov J, McCormick LL, Dillon CP, Green DR (2011) A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell 44:517–531

Loeppen S, Schneider D, Gaunitz F, Gebhardt R, Kurek R, Buchmann A, Schwarz M (2002) Overexpression of glutamine synthetase is associated with beta-catenin-mutations in mouse liver tumors during promotion of hepatocarcinogenesis by phenobarbital. Cancer Res 62:5685–5688

Loeppen S, Koehle C, Buchmann A, Schwarz M (2005) A beta-catenin-dependent pathway regulates expression of cytochrome P450 isoforms in mouse liver tumors. Carcinogenesis 26:239–2348

Lorber M, Patterson D, Huwe J, Kahn H (2009) Evaluation of background exposures of Americans to dioxin-like compounds in the 1990s and the 2000s. Chemosphere 77:640–51

Loscher W, Potschka H (2005) Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 6:591–602

Lu C, Li P, Gallegos R, Uttamsingh V, Xia CQ, Miwa GT, Balani SK, Gan LS (2006) Comparison of intrinsic clearance in liver microsomes and hepatocytes from rats and humans: evaluation of free fraction and uptake in hepatocytes. Drug Metab Dispos 34:1600–1605

Lubberstedt M, Muller-Vieira U, Mayer M, Biemel KM, Knospel F, Knobeloch D, Nussler AK, Gerlach JC, Zeilinger K (2011) HepaRG human hepatic cell line utility as a surrogate for primary human hepatocytes in drug metabolism assessment in vitro. J Pharmacol Toxicol Methods 63:59–68

Lucier GW, Tritscher A, Goldsworthy T, Foley J, Clark G, Goldstein J, Maronpot R (1991) Ovarian hormones enhance 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated increases in cell proliferation and preneoplastic foci in a two-stage model for rat hepatocarcinogenesis. Cancer Res 51:1391–1397

Luebeck EG, Buchmann A, Stinchcombe S, Moolgavkar SH, Schwarz M (2000) Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on initiation and promotion of GST-P-positive foci in rat liver: A quantitative analysis of experimental data using a stochastic model. Toxicol Appl Pharmacol 167:63–73

Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science 303:95–98

Lustig B, Behrens J (2003) The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol 129:199–221

Luthi AU, Martin SJ (2007) The CASBAH: a searchable database of caspase substrates. Cell Death Differ 14:641–650

Ly VT, Brock B (2011) Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. Chem Biol Interact 193:109–118

Lysz TW, Billiar TR, Curran RD, Simmons RL, Machiedo GW (1990) Kupffer cell-hepatocyte interactions and the changes in 1–14C-arachidonate incorporation in response to endotoxin in vitro. Prostaglandins 39:497–514

Ma PX, Zhang R (1999) Synthetic nano-scale fibrous extracellular matrix. J Biomed Mater Res 46:60–72

Macanas-Pirard P, Yaacob NS, Lee PC, Holder JC, Hinton RH, Kass GE (2005) Glycogen synthase kinase-3 mediates acetaminophen-induced apoptosis in human hepatoma cells. J Pharmacol Exp Ther 313:780–789

Macdougall JD, McCabe M (1967) Diffusion coefficient of oxygen through tissues. Nature 215:1173–1174

Mace K, Gonzalez FJ, McConnell IR, Garner RC, Avanti O, Harris CC, Pfeifer AM (1994) Activation of promutagens in a human bronchial epithelial cell line stably expressing human cytochrome P450 1A2. Mol Carcinog 11:65–73

Mace K, Aguilar F, Wang JS, Vautravers P, Gomez-Lechon M, Gonzalez FJ, Groopman J, Harris CC, Pfeifer AM (1997) Aflatoxin B1-induced DNA adduct formation and p53 mutations in CYP450-expressing human liver cell lines. Carcinogenesis 18:1291–1297

Machide M, Hashigasako A, Matsumoto K, Nakamura T (2006) Contact inhibition of hepatocyte growth regulated by functional association of the c-Met/hepatocyte growth factor receptor and LAR protein-tyrosine phosphatase. J Biol Chem 281:8765–8772

Mack AA, Kroboth S, Rajesh D, Wang WB (2011) Generation of induced pluripotent stem cells from CD34 + cells across blood drawn from multiple donors with non-integrating episomal vectors. PLoS One 6:e27956

Mackiewicz A, Ganapathi MK, Schultz D, Samols D, Reese J, Kushner I (1988) Regulation of rabbit acute phase protein biosynthesis by monokines. Biochem J 253:851–857

Maeda K, Ikeda Y, Fujita T, Yoshida K, Azuma Y, Haruyama Y, Yamane N, Kumagai Y, Sugiyama Y (2011) Identification of the rate-determining process in the hepatic clearance of atorvastatin in a clinical cassette microdosing study. Clin Pharmacol Ther 90:575–581

Maeda K, Shitara Y, Horie T, Sugiyama Y (2010) Web-based database as a tool to examine drug-drug interactions involving transporters. Springer, Berlin

Magalhães R, Nugraha B, Pervaiz S, Yu H, Kuleshova LL (2012) Influence of cell culture configuration on the post-cryopreservation viability of primary rat hepatocytes. Biomaterials 33:829–836

Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA (2002) Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646

Mahagita C, Grassl SM, Piyachaturawat P, Ballatori N (2007) Human organic anion transporter 1B1 and 1B3 function as bidirectional carriers and do not mediate GSH-bile acid cotransport. Am J Physiol Gastrointest Liver Physiol 293:G271–G278

Maher JJ, Lozier JS, Scott MK (1998) Rat hepatic stellate cells produce cytokine-induced neutrophil chemoattractant in culture and in vivo. Am J Physiol 275:G847–G853

Maier K, Hofmann U, Reuss M, Mauch K (2008) Identification of metabolic fluxes in hepatic cells from transient 13C-labeling experiments: part II. Flux estimation. Biotechnol Bioeng 100:355–370

Maier K, Hofmann U, Reuss M, Mauch K (2010) Dynamics and control of the central carbon metabolism in hepatoma cells. BMC Syst Biol 4:54

Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1365

Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR, Mangelsdorf DJ (2002) Vitamin D receptor as an intestinal bile acid sensor. Science 296:1313–1316

Malhi H, Gores GJ (2008) Cellular and molecular mechanisms of liver injury. Gastroenterology 134:1641–1654

Malhi H, Gores GJ, Lemasters JJ (2006) Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43:S31–S44

Malhi H, Barreyro FJ, Isomoto H, Bronk SF, Gores GJ (2007) Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut 56:1124–1131

Malhi H, Guicciardi ME, Gores GJ (2010) Hepatocyte death: a clear and present danger. Physiol Rev 90:1165–94

Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359:727–732

Malovic I, Sorensen KK, Elvevold KH, Nedredal GI, Paulsen S, Erofeev AV, Smedsrod BH, McCourt PA (2007) The mannose receptor on murine liver sinusoidal endothelial cells is the main denatured collagen clearance receptor. Hepatology 45:1454–1461

Mandard S, Muller M, Kersten S (2004) Peroxisome proliferator-activated receptor alpha target genes. Cell Mol Life Sci 61:393–416

Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531

Mareninova O, Shin JM, Vagin O, Turdikulova S, Hallen S, Sachs G (2005) Topography of the membrane domain of the liver Na + -dependent bile acid transporter. Biochemistry 44:13702–13712

Maronpot RR, Foley JF, Takahashi K, Goldsworthy T, Clark G, Tritscher A, Portier C, Lucier G (1993) Dose response for TCDD promotion of hepatocarcinogenesis in rats initiated with DEN: histologic, biochemical, and cell proliferation endpoints. Environ Health Perspect 101:634–642

Marquardt JU, Raggi C, Andersen JB, Seo D, Avital I, Geller D, Lee YH, Kitade M, Holczbauer A, Gillen MC, Conner EA, Factor VM, Thorgeirsson SS (2011) Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Hepatology 54:1031–1042

Marquart TJ, Allen RM, Ory DS, Baldan A (2010) miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci USA 107:12228–12232

Marquez B, van Bambeke F (2011) ABC multidrug transporters: target for modulation of drug pharmacokinetics and drug-drug interactions. Curr Drug Targets 12:600–620

Marquez RT, Wendlandt E, Galle CS, Keck K, McCaffrey AP (2010) MicroRNA-21 is upregulated during the proliferative phase of liver regeneration, targets Pellino-1, and inhibits NF-kappaB signaling. Am J Physiol Gastrointest Liver Physiol 298:G535–G5341

Marra F, Grandaliano G, Valente AJ, Abboud HE (1995) Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury. Hepatology 22:780–787

Martin-Armas M, Simon-Santamaria J, Pettersen I, Moens U, Smedsrod B, Sveinbjornsson B (2006) Toll-like receptor 9 (TLR9) is present in murine liver sinusoidal endothelial cells (LSECs) and mediates the effect of CpG-oligonucleotides. J Hepatol 44:939–946

Martin H, Sarsat JP, Lerche-Langrand C, Housset C, Balladur P, Toutain H, Albaladejo V (2002) Morphological and biochemical integrity of human liver slices in long-term culture: effects of oxygen tension. Cell Biol Toxicol 18:73–85

Martin AM, Nolan D, James I, Cameron P, Keller J, Moore C, Phillips E, Christiansen FT, Mallal S (2005) Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts. AIDS 19(1):97–99

Martin SF, Esser PR, Schmucker S, Dietz L, Naisbitt DJ, Park BK, Vocanson M, Nicolas JF, Keller M, Pichler WJ, Peiser M, Luch A, Wanner R, Maggi E, Cavani A, Rustemeyer T, Richter A, Thierse HJ, Sallusto F (2010) T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays. Cell Mol Life Sci 67:4171–4184

Martinez-Hernandez A, Amenta PS (1993) The hepatic extracellular matrix. I. Components and distribution in normal liver. Virchows Arch A Pathol Anat Histopathol 423:1–11

Martinez-Jimenez CP, Jover R, Donato MT, Castell JV, Gomez-Lechon MJ (2007) Transcriptional regulation and expression of CYP3A4 in hepatocytes. Curr Drug Metab 8:185–194

Martins PN, Theruvath TP, Neuhaus P (2008) Rodent models of partial hepatectomies. Liver Int 28:3–11

Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K (2002) Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 298:714–719

Massie I, Selden C, Morris J, Hodgson H, Fuller B (2011) Cryopreservation of encapsulated liver spheroids using a cryogen-free cooler: high functional recovery using a multi-step cooling profile. Cryo Letters 32:158–165

Masson MJ, Carpenter LD, Graf ML, Pohl LR (2008) Pathogenic role of natural killer T and natural killer cells in acetaminophen-induced liver injury in mice is dependent on the presence of dimethyl sulfoxide. Hepatology 48:889–897

Masubuchi Y (2006) Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab Pharmacokinet 21:347–356

Mathew LK, Simonich MT, Tanguay RL (2009) AHR-dependent misregulation of Wnt signaling disrupts tissue regeneration. Biochem Pharmacol 77:498–507

Mathijs K, Kienhuis AS, Brauers KJ, Jennen DG, Lahoz A, Kleinjans JC, van Delft JH (2009) Assessing the metabolic competence of sandwich-cultured mouse primary hepatocytes. Drug Metab Dispos 37:1305–1311

Matsui H, Takeuchi S, Osada T, Fujii T, Sakai Y (2012) Enhanced bile canaliculi formation enabling direct recovery of biliary metabolites of hepatocytes in 3D collagen gel microcavities. Lab Chip 12:1857–1864

Matsumura H, Shimizu Y, Ohsawa Y, Kawahara A, Uchiyama Y, Nagata S (2000) Necrotic death pathway in Fas receptor signaling. J Cell Biol 151:1247–1256

Mayhew BS, Jones DR, Hall SD (2000) An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation. Drug Metab Dispos 28:1031–1037

McClelland R, Wauthier E, Uronis J, Reid L (2008) Gradients in the liver’s extracellular matrix chemistry from periportal to pericentral zones: influence on human hepatic progenitors. Tissue Eng Part A 14:59–70

McCourt PA, Smedsrod BH, Melkko J, Johansson S (1999) Characterization of a hyaluronan receptor on rat sinusoidal liver endothelial cells and its functional relationship to scavenger receptors. Hepatology 30:1276–1286

McCullough CT, Tura BJ, Harrison DJ (2007) c-Myc partially mediates IFNgamma-induced apoptosis in the primary hepatocyte. Int J Exp Pathol 88:129–136

McCuskey RS, Bethea NW, Wong J, McCuskey MK, Abril ER, Wang X, Ito Y, Deleve LD (2005) Ethanol binging exacerbates sinusoidal endothelial and parenchymal injury elicited by acetaminophen. J Hepatol 42:371–377

McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, Beck PL, Muruve DA, Kubes P (2010) Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330:362–366

McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H (2012) The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 122:1574–1583

McGill MR, Yan HM, Ramachandran A, Murray GJ, Rollins DE, Jaeschke H (2011) HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. Hepatology 53:974–982

McGinnity DF, Soars MG, Urbanowicz RA, Riley RJ (2004) Evaluation of fresh and cryopreserved hepatocytes as in vitro drug metabolism tools for the prediction of metabolic clearance. Drug Metab Dispos 32:1247–1253

Meehan RR, Lewis JD, McKay S, Kleiner EL, Bird AP (1989) Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58:499–507

Meier PJ (1988) Transport polarity of hepatocytes. Semin Liver Dis 8:293–307

Meier PJ, Stieger B (2002) Bile salt transporters. Annu Rev Physiol 64:635–661

Meier PJ, Sztul ES, Reuben A, Boyer JL (1984) Structural and functional polarity of canalicular and basolateral plasma membrane vesicles isolated in high yield from rat liver. J Cell Biol 98:991–1000