S-adenosylmethionine induces mitochondrial dysfunction, permeability transition pore opening and redox imbalance in subcellular preparations of rat liver

Bianca Seminotti1, Ana Cristina Roginski1, Ângela Zanatta1, Alexandre Umpierrez Amaral2,1, Thabata Fernandes1, Kaleb Pinto Spannenberger1, Lucas Henrique Rodrigues da Silva1, Rafael Teixeira Ribeiro1, Guilhian Leipnitz3,1, Moacir Wajner3,1,4
1Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
2Departamento de Ciências Biológicas, Universidade Regional Integrada do Alto Uruguai e das Missões, Erechim, Brazil
3Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
4Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

Tóm tắt

S-adenosylmethionine (AdoMet) predominantly accumulates in tissues and biological fluids of patients affected by liver dysmethylating diseases, particularly glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies, as well as in some hepatic mtDNA depletion syndromes, whose pathogenesis of liver dysfunction is still poorly established. Therefore, in the present work, we investigated the effects of S-adenosylmethionine (AdoMet) on mitochondrial functions and redox homeostasis in rat liver. AdoMet decreased mitochondrial membrane potential and Ca2+ retention capacity, and these effects were fully prevented by cyclosporin A and ADP, indicating mitochondrial permeability transition (mPT) induction. It was also verified that the thiol-alkylating agent NEM prevented AdoMet-induced ΔΨm dissipation, implying a role for thiol oxidation in the mPT pore opening. AdoMet also increased ROS production and provoked protein and lipid oxidation. Furthermore, AdoMet reduced GSH levels and the activities of aconitase and α-ketoglutarate dehydrogenase. Free radical scavengers attenuated AdoMet effects on lipid peroxidation and GSH levels, supporting a role of ROS in these effects. It is therefore presumed that disturbance of mitochondrial functions associated with mPT and redox unbalance may represent relevant pathomechanisms of liver damage provoked by AdoMet in disorders in which this metabolite accumulates.

Từ khóa


Tài liệu tham khảo

Akerman KE, Wikstrom MK (1976) Safranine as a probe of the mitochondrial membrane potential. FEBS Lett 68:191–197. https://doi.org/10.1016/0014-5793(76)80434-6

Aksenov MY, Markesbery WR (2001) Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer’s disease. Neurosci Lett 302:141–145. https://doi.org/10.1016/s0304-3940(01)01636-6

Ansorena E, García-Trevijano ER, Martínez-Chantar ML, Huang ZZ, Chen L, Mato JM, Iraburu M, Lu SC, Avila MA (2002) S-adenosylmethionine and methylthioadenosine are antiapoptotic in cultured rat hepatocytes but proapoptotic in human hepatoma cells. Hepatology 35:274–280. https://doi.org/10.1053/jhep.2002.30419

Ara AI, Xia M, Ramani K, Mato JM, Lu SC (2008) S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation. Hepatology 47:1655–1666. https://doi.org/10.1002/hep.22231

Augoustides-Savvopoulou P, Luka Z, Karyda S, Stabler SP, Allen RH, Patsiaoura K, Wagner C, Mudd SH (2003) Glycine N-methyltransferase deficiency: a new patient with a novel mutation. J Inherit Metab Dis 26:745–759. https://doi.org/10.1023/B:BOLI.0000009978.17777.33

Barić I, Fumic K, Glenn B, Cuk M, Schulze A, Finkelstein JD, James SJ, Mejaski-Bosnjak V, Pazanin L, Pogribny IP, Rados M, Sarnavka V, Scukanec-Spoljar M, Allen RH, Stabler S, Uzelac L, Vugrek O, Wagner C, Zeisel S, Mudd SH (2004) S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Proc Natl Acad Sci USA 101:4234–4239. https://doi.org/10.1073/pnas.0400658101

Barić I, Ćuk M, Fumić K, Vugrek O, Allen RH, Glenn B, Maradin M, Pazanin L, Pogribny I, Rados M, Sarnavka V, Schulze A, Stabler S, Wagner C, Zeisel SH, Mudd SH (2005) S-adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy. J Inherit Metab Dis 28:885–902. https://doi.org/10.1007/s10545-005-0192-9

Barić I, Staufner C, Augoustides-Savvopoulou P, Chien YH, Dobbelaere D, Grünert SC, Opladen T, Petković Ramadža D, Rakić B, Wedell A, Blom HJ (2017a) Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders. J Inherit Metab Dis 40:5–20. https://doi.org/10.1007/s10545-016-9972-7

Barić I, Erdol S, Saglam H, Lovrić M, Belužić R, Vugrek O, Blom HJ, Fumić K (2017b) Glycine N-methyltransferase deficiency: A member of dysmethylating liver disorders? JIMD Rep 31:101–106. https://doi.org/10.1007/8904_2016_543

Bas H, Cilingir O, Tekin N, Saylisoy S, Durak Aras B, Uzay E, Erzurumluoglu Gokalp E, Artan S (2020) Turkish patient with novel AHCY variants and presumed diagnosis of S-adenosylhomocysteine hydrolase deficiency. Am J Med Genet A 182:740–745. https://doi.org/10.1002/ajmg.a.61489

Bjursell MK, Blom HJ, Cayuela JA, Engvall ML, Lesko N, Balasubramaniam S, Brandberg G, Halldin M, Falkenberg M, Jakobs C, Smith D, Struys E, von Döbeln U, Gustafsson CM, Lundeberg J, Wedell A (2011) Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. Am J Hum Genet 89:507–515. https://doi.org/10.1016/j.ajhg.2011.09.004

Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Methods Mol Biol 108:347–352. https://doi.org/10.1385/0-89603-472-0:347

Buist NR, Glenn B, Vugrek O, Wagner C, Stabler S, Allen RH, Pogribny I, Schulze A, Zeisel SH, Barić I, Mudd SH (2006) S-adenosylhomocysteine hydrolase deficiency in a 26-year-old man. J Inherit Metab Dis 29:538–545. https://doi.org/10.1007/s10545-006-0240-0

Cantoni GL (1952) The nature of the active methyl donor formed enzymatically from L-methionine and adenosinetriphosphate. J Am Chem Soc 74:2942–2943. https://doi.org/10.1021/ja01131a519

Cave M, Deaciuc I, Mendez C, Song Z, Joshi-Barve S, Barve S, McClain C (2007) Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem 18:184–195. https://doi.org/10.1016/j.jnutbio.2006.12.006

Cecatto C, Amaral AU, Wajner A, Wajner SM, Castilho RF, Wajner M (2020) Disturbance of mitochondrial functions associated with permeability transition pore opening induced by cis-5-tetradecenoic and myristic acids in liver of adolescent rats. Mitochondrion 50:1–13. https://doi.org/10.1016/j.mito.2019.09.008

Cederbaum AI (2010) Hepatoprotective effects of S-adenosyl-L-methionine against alcohol- and cytochrome P450 2E1-induced liver injury. World J Gastroenterol 16:1366–1376. https://doi.org/10.3748/wjg.v16.i11.1366

Costantini P, Chernyak BV, Petronilli V, Bernardi P (1996) Modulation of the mitochondrial permeability transition pore by pyridine nucleotides and dithiol oxidation at two separate sites. J Biol Chem 271:6746–6751. https://doi.org/10.1074/jbc.271.12.6746

Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R (2003) Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 329:23–38. https://doi.org/10.1016/s0009-8981(03)00003-2

Esterbauer H, Cheeseman KH (1990) Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods Enzymol 186:407–421. https://doi.org/10.1016/0076-6879(90)86134-H

Evelson P, Travacio M, Repetto M, Escobar J, Llesuy S, Lissi EA (2001) Evaluation of total reactive antioxidant potential (TRAP) of tissue homogenates and their cytosols. Arch Biochem Biophys 388:261–266. https://doi.org/10.1006/abbi.2001.2292

Fagian MM, Pereira-da-Silva L, Martins IS, Vercesi AE (1990) Membrane protein thiol cross-linking associated with the permeabilization of the inner mitochondrial membrane by Ca2+ plus prooxidants. J Biol Chem 265:19955–19960

Fedorova M, Griesser E, Vemula V, Weber D, Ni Z, Hoffmann R (2014) Protein and lipid carbonylation in cellular model of nitrosative stress: mass spectrometry, biochemistry and microscopy study. Free Radic Biol Med 75:S15. https://doi.org/10.1016/j.freeradbiomed.2014.10.589

Finkelstein JD (1990) Methionine metabolism in mammals. J Nutr Biochem 1:228–237. https://doi.org/10.1016/0955-2863(90)90070-2

Finkelstein JD, Kyle W, Harris BJ (1971) Methionine metabolism in mammals. Regulation of homocysteine methyltransferases in rat tissue. Arch Biochem Biophys 146:84–92. https://doi.org/10.1016/S0003-9861(71)80044-9

Galano A, Reiter RJ (2018) Melatonin and its metabolites vs oxidative stress: from individual actions to collective protection. J Pineal Res 65:e12514. https://doi.org/10.1111/jpi.12514

Halliwell B, Gutteridge JMC (2015) Cellular responses to oxidative stress: adaptation, damage, repair, senescence and death. In: Halliwell B, Gutteridge JMC (eds) Free radicals in biology and medicine, 5th edn. Oxford University Press Inc., Oxford, pp 199–283

Kalyanaraman B, Darley-Usmar V, Davies KJ, Dennery PA, Forman HJ, Grisham MB, Mann GE, Moore K, Roberts LJ 2nd, Ischiropoulos H (2012) Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic Biol Med 52:1–6. https://doi.org/10.1016/j.freeradbiomed.2011.09.030

Ko K, Yang HP, Noureddin M, Iglesia-Ara A, Xia M, Wagner C, Luka Z, Mato JM, Lu SC (2008) Changes in S-adenosylmethionine and glutathione homeostasis during endotoxemia in mice. Lab Investig 88:1121–1129. https://doi.org/10.1038/labinvest.2008.69

Latasa MU, Boukaba A, García-Trevijano ER, Torres L, Rodríguez JL, Caballería J, Lu SC, López-Rodas G, Franco L, Mato JM, Avila MA (2001) Hepatocyte growth factor induces MAT2A expression and histone acetylation in rat hepatocytes: role in liver regeneration. FASEB J 15:1248–1250. https://doi.org/10.1096/fj.00-0556fjev1

LeBel CP, Ischiropoulos H, Bondy SC (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227–231. https://doi.org/10.1021/tx00026a012

Leipnitz G, Vargas CR, Wajner M (2015) Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. J Inherit Metab Dis 38:1021–1028. https://doi.org/10.1007/s10545-015-9863-3

Lenartowicz E, Bernardi P, Azzone GF (1991) Phenylarsine oxide induces the cyclosporin A-sensitive membrane permeability transition in rat liver mitochondria. J Bioenerg Biomembr 23:679–688. https://doi.org/10.1007/BF00785817

Leonard SS, Xia C, Jiang BH, Stinefelt B, Klandorf H, Harris GK, Shi X (2003) Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem Biophys Res Commun 309:1017–1026. https://doi.org/10.1016/j.bbrc.2003.08.105

Li TWH, Zhang Q, Oh P, Xia M, Chen H, Bemanian S, Lastra N, Circ M, Moyer MP, Mato JM, Aw TY, Lu SC (2009) S-adenosylmethionine and methylthioadenosine inhibit cellular FLICE inhibitory protein expression and induce apoptosis in colon cancer cells. Mol Pharmacol 76:192–200. https://doi.org/10.1124/mol.108.054411

Liang LP, Waldbaum S, Rowley S, Huang TT, Day BJ, Patel M (2012) Mitochondrial oxidative stress and epilepsy in SOD2 deficient mice: attenuation by a lipophilic metalloporphyrin. Neurobiol Dis 45:1068–1076. https://doi.org/10.1016/j.nbd.2011.12.025

Loenen WA (2006) S-adenosylmethionine: Jack of all trades and master of everything? Biochem Soc Trans 34:330–333. https://doi.org/10.1042/BST20060330

Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

Lu SC, Mato JM (2012) S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev 92:1515–1542. https://doi.org/10.1152/physrev.00047.2011

Lushchak OV, Piroddi M, Galli F, Lushchak VI (2014) Aconitase post-translational modification as a key in linkage between Krebs cycle, iron homeostasis, redox signaling, and metabolism of reactive oxygen species. Redox Rep 19:8–15. https://doi.org/10.1179/1351000213Y.0000000073

Menezes-Filho SL, Amigo I, Prado FM, Ferreira NC, Koike MK, Pinto IFD, Miyamoto S, Montero EFS, Medeiros MHG, Kowaltowski AJ (2017) Caloric restriction protects livers from ischemia/reperfusion damage by preventing Ca2+-induced mitochondrial permeability transition. Free Radic Biol Med 110:219–227. https://doi.org/10.1016/j.freeradbiomed.2017.06.013

Mirandola SR, Melo DR, Schuck PF, Ferreira GC, Wajner M, Castilho RF (2008) Methylmalonate inhibits succinate-supported oxygen consumption by interfering with mitochondrial succinate uptake. J Inherit Metab Dis 31:44–54. https://doi.org/10.1007/s10545-007-0798-1

Moore CL (1971) Specific inhibition of mitochondrial Ca++ transport by ruthenium red. Biochem Biophys Res Commun 42:298–305. https://doi.org/10.1016/0006-291X(71)90102-1

Morrison JF (1954) The activation of aconitase by ferrous ions and reducing agents. Biochem J 58:685–692. https://doi.org/10.1042/bj0580685

Mudd SH, Cerone R, Schiaffino MC, Fantasia AR, Minniti G, Caruso U, Lorini R, Watkins D, Matiaszuk N, Rosenblatt DS, Schwahn B, Rozen R, LeGros L, Kotb M, Capdevila A, Luka Z, Finkelstein JD, Tangerman A, Stabler SP, Allen RH, Wagner C (2001) Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninemia. J Inherit Metab Dis 24:448–464. https://doi.org/10.1023/a:1010577512912

Mudd SH, Brosnan JT, Brosnan ME, Jacobs RL, Stabler SP, Allen RH, Vance DE, Wagner C (2007) Methyl balance and transmethylation fluxes in humans. Am J Clin Nutr 85:19–25. https://doi.org/10.1093/ajcn/85.1.19

Mudd SH, Wagner C, Luka Z, Stabler SP, Allen RH, Schroer R, Wood T, Wang J, Wong LJ (2012) Two patients with hepatic mtDNA depletion syndromes and marked elevations of S-adenosylmethionine and methionine. Mol Genet Metab 105:228–236. https://doi.org/10.1016/j.ymgme.2011.11.006

Myhre O, Andersen JM, Aarnes H, Fonnum F (2003) Evaluation of the probes 2’,7’-dichlorofluorescin diacetate, luminol, and lucigenin as indicators of reactive species formation. Biochem Pharmacol 65:1575–1582. https://doi.org/10.1016/S0006-2952(03)00083-2

Navarro-Gonzálvez JA, Garcia-Benayas C, Arenas J (1998) Semiautomated measurement of nitrate in biological fluids. Clin Chem 44:679–681

Noureddin M, Sander-Struckmeier S, Mato JM (2020) Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: a systematic review. World J Hepatol 12:46–63. https://doi.org/10.4254/wjh.v12.i2.46

Orioli M, Aldini G, Beretta G, Facino RM, Carini M (2005) LC-ESI-MS/MS determination of 4-hydroxy-trans-2-nonenal Michael adducts with cysteine and histidine-containing peptides as early markers of oxidative stress in excitable tissues. J Chromatogr B Analyt Technol Biomed Life Sci 827:109–118. https://doi.org/10.1016/j.jchromb.2005.04.025

Pan X, Liu J, Nguyen T, Liu C, Sun J, Teng Y, Fergusson MM, Rovira II, Allen M, Springer DA, Aponte AM, Gucek M, Balaban RS, Murphy E, Finkel T (2013) The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat Cell Biol 15:1464–1472. https://doi.org/10.1038/ncb2868

Patel M (2004) Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures. Free Radic Biol Med 37:1951–1962. https://doi.org/10.1016/j.freeradbiomed.2004.08.021

Pendin D, Greotti E, Pozzan T (2014) The elusive importance of being a mitochondrial Ca(2+) uniporter. Cell Calcium 55:139–145. https://doi.org/10.1016/j.ceca.2014.02.008

Rakic B, Sinclair G, Stockler S, Vallance H (2015) Is glycine N-methyltransferase (GNMT) deficiency underdiagnosed? In: Garrod symposium “metabolic medicine in motion. book of abstracts, Vancouver, p 114

Rasola A, Bernardi P (2011) Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis. Cell Calcium 50:222–233. https://doi.org/10.1016/j.ceca.2011.04.007

Reznick AZ, Packer L (1994) Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol 233:357–363. https://doi.org/10.1016/s0076-6879(94)33041-7

Roginski AC, Wajner A, Cecatto C, Wajner SM, Castilho RF, Wajner M, Amaral AU (2020) Disturbance of bioenergetics and calcium homeostasis provoked by metabolites accumulating in propionic acidemia in heart mitochondria of developing rats. Biochim Biophys Acta Mol Basis Dis 1866:165682. https://doi.org/10.1016/j.bbadis.2020.165682

Saito A, Castilho RF (2010) Inhibitory effects of adenine nucleotides on brain mitochondrial permeability transition. Neurochem Res 35:1667–1674. https://doi.org/10.1007/s11064-010-0228-x

Schweinberger BM, Wyse AT (2016) Mechanistic basis of hypermethioninemia. Amino Acids 48:2479–2489. https://doi.org/10.1007/s00726-016-2302-4

Seminotti B, Zanatta Â, Ribeiro RT, da Rosa MS, Wyse ATS, Leipnitz G, Wajner M (2019) Disruption of brain redox homeostasis, microglia activation and neuronal damage induced by intracerebroventricular administration of S-adenosylmethionine to developing rats. Mol Neurobiol 56:2760–2773. https://doi.org/10.1007/s12035-018-1275-6

Seminotti B, da Silva JC, Ribeiro RT, Leipnitz G, Wajner M (2020) Free radical scavengers prevent argininosuccinic acid-induced oxidative stress in the brain of developing rats: A new adjuvant therapy for argininosuccinate lyase deficiency? Mol Neurobiol 57:1233–1244. https://doi.org/10.1007/s12035-019-01825-0

Starkov AA (2013) An update on the role of mitochondrial α-ketoglutarate dehydrogenase in oxidative stress. Mol Cell Neurosci 55:13–16. https://doi.org/10.1016/j.mcn.2012.07.005

Staufner C, Lindner M, Dionisi-Vici C, Freisinger P, Dobbelaere D, Douillard C, Makhseed N, Straub BK, Kahrizi K, Ballhausen D, la Marca G, Kölker S, Haas D, Hoffmann GF, Grünert SC, Blom HJ (2016) Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options. J Inherit Metab Dis 39:273–283. https://doi.org/10.1007/s10545-015-9904-y

Stender S, Chakrabarti RS, Xing C, Gotway G, Cohen JC, Hobbs HH (2015) Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency. Mol Genet Metab 116:269–274. https://doi.org/10.1016/j.ymgme.2015.10.009

Strauss KA, Ferreira C, Bottiglieri T, Zhao X, Arning E, Zhang S, Zeisel SH, Escolar ML, Presnick N, Puffenberger EG, Vugrek O, Kovacevic L, Wagner C, Mazariegos GV, Mudd SH, Soltys K (2015) Liver transplantation for treatment of severe S-adenosylhomocysteine hydrolase deficiency. Mol Genet Metab 116:44–52. https://doi.org/10.1016/j.ymgme.2015.06.005

Tanveer A, Virji S, Andreeva L, Totty NF, Hsuan JJ, Ward JM, Crompton M (1996) Involvement of cyclophilin D in the activation of a mitochondrial pore by Ca2+ and oxidant stress. Eur J Biochem 238:166–172. https://doi.org/10.1111/j.1432-1033.1996.0166q.x

Tretter L, Adam-Vizi V (2000) Inhibition of Krebs cycle enzymes by hydrogen peroxide: a key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. J Neurosci 20:8972–8979. https://doi.org/10.1523/JNEUROSCI.20-24-08972.2000

Tretter L, Adam-Vizi V (2004) Generation of reactive oxygen species in the reaction catalyzed by alpha-ketoglutarate dehydrogenase. J Neurosci 24:7771–7778. https://doi.org/10.1523/JNEUROSCI.1842-04.2004

Tretter L, Adam-Vizi V (2005) Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond B Biol Sci 360:2335–2345. https://doi.org/10.1098/rstb.2005.1764

Valle VG, Fagian MM, Parentoni LS, Meinicke AR, Vercesi AE (1993) The participation of reactive oxygen species and protein thiols in the mechanism of mitochondrial inner membrane permeabilization by calcium plus prooxidants. Arch Biochem Biophys 307:1–7. https://doi.org/10.1006/abbi.1993.1551

Vasquez-Vivar J, Kalyanaraman B, Kennedy MC (2000) Mitochondrial aconitase is a source of hydroxyl radical. An electron spin resonance investigation. J Biol Chem 275:14064–14069. https://doi.org/10.1074/jbc.275.19.14064

Vercesi AE, Castilho RF, Kowaltowski AJ, de Oliveira HCF, de Souza-Pinto NC, Figueira TR, Busanello ENB (2018) Mitochondrial calcium transport and the redox nature of the calcium-induced membrane permeability transition. Free Radic Biol Med 29:1–24. https://doi.org/10.1016/j.freeradbiomed.2018.08.034

Watson WH, Zhao Y, Chawla RK (1999) S-adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumour necrosis factor alpha. Biochem J 342:21–25

Yang H, Sadda MR, Li M, Zeng Y, Chen L, Bae W, Ou X, Runnegar MT, Mato JM, Lu SC (2004) S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x(S). Hepatology 40:221–231. https://doi.org/10.1002/hep.20274

Yang HP, Ramani K, Xia M, Ko KS, Li TWH, Oh P, Li J, Lu SC (2009) Dysregulation of glutathione synthesis during cholestasis in mice: molecular mechanisms and therapeutic implications. Hepatology 49:1982–1991. https://doi.org/10.1002/hep.22908

Zanatta Â, Cecatto C, Ribeiro RT, Amaral AU, Wyse AT, Leipnitz G, Wajner M (2018) S-adenosylmethionine promotes oxidative stress and decreases Na+, K+-ATPase activity in cerebral cortex supernatants of adolescent rats: implications for the pathogenesis of S-adenosylhomocysteine hydrolase deficiency. Mol Neurobiol 55:5868–5878. https://doi.org/10.1007/s12035-017-0804-z