Acylcarnitines in intermediary metabolism
Tóm tắt
From the time of its discovery in 1905 until the first description of its deficiency in 1973, the role of carnitine in intermediary metabolism was decidedly vague. Identification of carnitine acyl transferases and their products, acylcarnitines, have paved the way to the confirmation of the importance of carnitine in the transfer of fatty acid CoAs into the mitochondrion for β-oxidation and energy production. The elucidation of defects in fatty acid oxidation together with the concept of carnitine therapy in certain organoacidaemias have given a new meaning to the term acylcarnitine. Not only are these compounds of diagnostic importance, their formation may be part of a secondary carnitine depletion which may be brought about as a result of various medications. Recent evidence suggests that long-chain acylcarnitines are responsible for cardiac arrhythmias and other effects, both good and bad, will certainly be found. This review will attempt to highlight the importance of acylcarnitines, from their production, the difficulties in analysis, the diagnostic possibilities and their positive and negative effects on intermediary metabolism.
Tài liệu tham khảo
Bartels GL, Remme WJ, Pillay M, Schönfeld DHW, Cox PH, Kruijssen HACM, Knufman NMJ (1992) Acute improvement of cardiac function with intravenous L-propionylcarnitine in humans. J Cardiovasc Pharmacol 20: 157–164
Bhuiyan AK, Watmough N, Turnbull DM, Aynsley-Green A, Leonard JV, Bartlett K (1987) The detection of octanoyl-L-carnitine by high performance thin layer chromatography—a simple screening method for the diagnosis of medium-chain acyl-CoA dehydrogenase deficiency. Clin Chim Acta 165: 39–44
Bieber LL (1988) Carnitine. Ann Rev Biochem 57: 261–283
Böhles H, Evangeliou A, Bervoets K, Eckert I, Sewell AC (1994) Carnitine esters in metabolic disease. Eur J Pediatr 153 [Suppl 1]: S57-S61
Böhles H, Noppeney T, Akcetin Z, Rein J, Emde J von der (1986) The effect of pre-operative L-carnitine supplementation on myocardial metabolism during aorto-coronary-bypass surgery. Curr Ther Res 39: 429–435
DaTorre SD, Creer MH, Pogwizd SM, Corr PB (1991) Amphipathic lipid metabolites and their relation to arrhythmogenesis in the ischemic heart. J Mol Cell Cardiol 23: 11–22
Dhalla NS, Dixon IMC, Shah KR, Ferrari R (1992) Beneficial effects of L-carnitine and derivatives on heart membranes in experimental diabetes. In: Ferrari R, DiMauro S, Sherwood G (eds) L-Carnitine and its role in medicine: from function to therapy. Academic Press, London, pp 411–426
Duran M, Mitchell G, Klerk JBC de (1985) Octanoic acidemia and octanoylcarnitine excretion with dicarboxylic aciduria due to defective oxidation of medium-chain fatty acids. J Pediatr 107: 397–404
Farquharson J, Cherry Jamieson E, Muir J, Cockburn F, Logan RW (1992) Direct gas chromatographic assay of urinary medium-chain acylcarnitines by their thermal decomposition. Clin Chim Acta 205: 233–240
Fischbach PS, Corr PB, Yamada KA (1992) Long-chain acylcarnitine increases intracellular Ca++ and induces after depolarisation in adult ventricular myocytes. Circulation 96: 748
Fishlock RC, Bieber LL, Snoswell AM (1984) Sources of error in determination of carnitine and acylcarnitine in plasma. Clin Chem 30: 316–318
Ghidini O, Azurro M, Vita G, Sartori G (1988) Evaluation of the therapeutic efficacy of L-carnitine in congestive heart failure. J Clin Pharmacol Ther Toxicol 26: 217–220
Huang ZH, Gage DA, Bieber LL, Sweeley CC (1991) Analysis of acylcarnitines as their N-demethylated ester derivatives by gas chromatography-chemical ionisation mass spectrometry. Anal Biochem 199: 98–105
Kumps A, Duez P, Mardens Y (1994) Gas chromatographic profiling and determination of urinary acylcarnitines. J Chromatog B 658: 241–248
Lecluyse EL, Sutton SC, Fix JA (1993) In vitro effects of long-chain acylcarnitines on the permeability, transepithelial electrical resistance and morphology of rat colonic mucosa. J Pharmacol Exp Ther 265: 955–962
Lehotay DC, Fischer LJ (1991) Sodium pivalate-induced carnitine deficiency in rats and guinea pigs. 2nd International Symposium on Clinical, Biochemical and Molecular Aspects of Fatty Acid Oxidation. Philadelphia USA, 3–6 November 1991
Liedtke AJ, De Maison L, Nellis SH (1988) Effects of L-propionylcarnitine on mechanical recovery during reflow in intact hearts. Am J Physiol 255: H169-H176
Lowes S, Rose ME (1990) Simple and unambiguous method for identifying urinary acylcarnitines using gas chromatography-mass spectrometry. Analyst 115: 511–516
Mancini M, Rengo F, Lingetti M, Sorrentino GP, Nolfe G (1992) Controlled study on the therapeutic efficacy of propionyl-L-carnitine in patients with congestive heart failure. Arzneimittelforschung 42: 1101–1104
Melegh B, Kerner J, Bieber LL (1987) Pivampicillin-promoted excretion of pivaloylcarnitine in humans. Biochem Pharmacol 36: 3405–3409
McGarry JD, Foster DW (1976) An improved and simplified radioisotopic assay for the determination of free and esterified carnitine. J Lipid Res 17: 277–281
Millington DS, Roe CR, Maltby DA (1984) Application of high resolution fast atom bombardment and constant B/E ratio linked scanning to the identification and analysis of acylcarnitines in metabolic disease. Biomed Mass Spectrom 11: 236–241
Millington DS, Bohan TP, Roe CR, Yergey AL, Liberato DJ (1985) Valproylcarnitine: a novel drug metabolite identified by fast atom bombardment and thermospray liquid chromatography mass spectrometry. Clin Chim Acta 145: 69–76
Millington DS, Roe CR, Maltby DA (1987) Characterization of new diagnostic acylcarnitines in patients with β-ketothiolase deficiency and glutaric aciduria type I using mass spectrometry. Biomed Environm Mass Spectrom 14: 711–716
Millington DS, Norwood DL, Kodo N, Roe CR, Inoue F (1989) Application of fast atom bombardment with tandem mass spectrometry to the analysis of acylcarnitines in human urine, blood and tissue. Anal Biochem 180: 331–339
Minkler PE, Ingalls ST, Hoppel CL (1990) High performance liquid chromatographic separation of acylcarnitines following derivatisation with 4′-bromophenacyl trifluoromethansulfonate. Anal Biochem 185: 29–35
Moore R, Millington DS, Norwood D, Kodo N, Robinson P, Glasgow JFT (1990) Identification of phenylpropionylcarnitine, a new metabolite of phenylpropionic acid in a patient with medium-chain acyl-CoA dehydrogenase deficiency. J Inherited Metab Dis 13: 325–329
Morrow RJ, Rose ME (1992) Isolation of acylcarnitines from urine: a comparison of methods and application to long-chain acyl-CoA dehydrogenase deficiency. Clin Chim Acta 211: 73–81
Muranishi S (1990) Absorption enhancers. Crit Rev Ther Drug Carrier Syst 7: 1–33
Olbrich HG, Evangeliou A, Tabatabaei SB, Cieslinski G, Hartmann A, Beyersdorf F, Herrmann G, Böhles HJ (1994) Correlation between long-chain acylcarnitine in serum and myocardium after heart transplantation in humans. Am J Clin Nutr 60: 414–417
Paulson DJ, Traxler J, Schmidt M, Noonan J, Shug AL (1986) Protection of the ischemic myocardium by L-propionyl carnitine: effects on the recovery of cardiac output after ischaemia and reperfusion, carnitine transports and fatty acid oxidation. Cardiovasc Res 20: 536–541
Pearson DJ, Tubbs PK (1964) Tissue levels of acid-insoluble carnitine in rat heart. Biochim Biophys Acta 84: 772–773
Pryzrembel H, Sewell AC (1995) Defects in long-chain fatty acid oxidation as a cause of cardiomyopathy. In: Böhles H, Hofstetter RM, Sewell AC (eds) Metabolic cardiomyopathy. Wissenschaftlicher Verlag, Stuttgart (in press)
Regitz V, Shug AL, Fleck E (1990) Defective myocardial carnitine metabolism in congestive heart failure secondary to dilated cardiomyopathy and to coronary, hypertensive and valvular heart diseases. Am J Cardiol 65: 755–760
Roe CR, Millington DS, Malthy DA, Kahler SG, Bohan TP (1984) L-Carnitine therapy in isovaleric acidemia. J Clin Invest 74: 2290–2295
Roe CR, Millington DS, Maltby DA, Bohan TP, Hoppel CL (1984) L-Carnitine enhances excretion of propionyl coenzyme A as propionylcarnitine in propionic acidemia. J Clin Invest 73: 1785–1788
Roe CR, Millington DS, Maltby DA, Bohan TP, Kahler SG, Chalmers RA (1985) Diagnostic and therapeutic implications of medium-chain acylcarnitines in medium-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 19: 459–466
Roe CR, Millington DS, Maltby DA (1986) Identification of 3-methylglutarylcarnitine. A new diagnostic metabolite of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. J Clin Invest 77: 1391–1394
Roe CR, Millington DS, Kahler SG, Kodo N, Norwood DL (1991) Carnitine and the organic acidemias. In: Schaub J, Van Hoof F, Vis HL (eds) Inborn errors of metabolism. Nestle Nutrition Workshop Series Vol 24, Raven Press, New York, pp 57–70
Sato T, Kiyosue T, Arita M (1992) Inhibitory effects of palmitoylcarnitine and lysophosphatidylcholine on the sodium current of cardiac ventricular cells. Pflugers Arch 420: 94–100
Schlenzig JS, Poggi-Travert F, Laurent J, Jan D, Jouvet P, Beringer A, Rabier D, Wendel U, Sewell AC, Revillon Y, Kamoun P, Saudubray JM (1994) Liver transplantation in two cases of propionic acidemia-metabolic evidence for persistence of metabolites. VI International Congress Inborn Errors of Metabolism, Milan 27–31 May, p 208
Schlenzig JS, Charpentier C, Rabier D, Kamoun P, Sewell AC, Harpey JP (1995) L-Carnitine: a way to decrease cellular toxicity of ifosfamide? Eur J Pediatr (in press)
Schmidt-Sommerfeld E, Penn D, Kerner J, Bieber LL, Rossi TM, Lebenthal E (1989) Quantitation of urinary carnitine esters in a patient with medium-chain acyl-coenzyme A dehydrogenase deficiency: effect of metabolic state and L-carnitine therapy. J Pediatr 115: 577–582
Schmidt-Sommerfeld E, Penn D, Rinaldo P, Kossak BD, Li BK, Huang ZH, Gage DA (1992) Urinary medium-chain acylcarnitines in medium-chain acyl-CoA dehydrogenase deficiency, medium-chain triglyceride feeding and valproic acid therapy: sensitivity and specificity of the radioisotopic exchange/high performance liquid chromatography method. Pediatr Res 6: 545–551
Sekas G, Paul HS (1991) Pyrimethamine and sulfadiazine administration produces carnitine deficiency. Carnitine Symposium, Atlanta, USA 19–21 April
Sewell AC, Bender SW, Wirth S, Münterfering H, Iljist L, Wanders RJA (1994) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a severe fatty acid oxidation disorder. Eur J Pediatr 153: 745–750
Shigematsu Y, Bykov IL, Liu YY, Kikawa Y, Sudo M, Fujioka M (1994) Acylcarnitine profile in tissues and body fluids of biotin-deficient rats with and without L-carnitine supplementation. J Inherited Metab Dis 17: 678–690
Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91: 10771–10778
Silliprandi N, Di Lisa F, Pivetta A, Miotto G, Silliprandi D (1987) Transport and function of L-carnitine and propionyl-L-carnitine: relevance to some cardiomyopathies and cardiac ischemia. Z Kardiol 76 [Suppl 5]: 34–40
Silliprandi N, Sartorelli L, Ciman M, Di Lisa F (1989) Carnitine: metabolism and clinical chemistry. Clin Chim Acta 183: 3–12
Sutton SC, LeCluyse EL, Cammack LA, Fix JA (1992) Enhanced bioavailability of cefoxitin using palmitoyl-L-carnitine. I. effects of intestinal region and sample localisation on absorption promoter activity. Pharm res 9: 191–194
Van Bocxlaer JF, De Leenheet AP (1993) Solid-phase extraction technique for gas-chromatographic profiling of acylcarnitines. Clin Chem 39: 1911–1917
Van Kempen TATG, Odle J (1992) Quantification of carnitine esters by high performance liquid chromatography. Effect of feeding medium-chain triglycerides on the plasma carnitine ester profile. J Chromatog 584: 157–165
Wu J, McHowat J, Saffitz JE, Yamada KA, Corr PB (1993) Inhibition of gap junctional conductance by long-chain acylcarnitines and their preferential accumulation in junctional sarcolemma during hypoxia. Circ Res 72: 879–889
Yamada KA, McHowat J, Yan GX, Donahue K, Peirick J, Kleber AG, Corr PB (1994) Cellular uncoupling induced by accumulation of long-chain acylcarnitine during ischemia. Circ Res 74: 83–95