THE ROLE OF CYTOCHROME P450 ISOFORMS OF HEPATOCYTE ENDOPLASMIC RETICULUM IN ETHANOL METABOLISM
Abstract
Background. Three metabolic pathways that can function simultaneously are known to be involved in ethanol oxidation in the liver: alcohol dehydrogenase pathway, microsomal ethanol-oxidizing system, and catalase pathway. Though the cytochrome P450-dependent microsomal ethanol-oxidizing system plays an insignificant role in metabolism of small amounts of ethanol, it is induced in case of ethanol excess and becomes essential when ethanol is abused. The main components of this system are cytochrome P450 (CYP) isoforms of smooth endoplasmic reticulum. Objective. To characterize the role of the key isoforms of cytochrome P450 in ethanol oxidation. Material and methods. We carried out an analysis of modern literature data on the role of the main isoforms of cytochrome P450 in liver metabolism of ethanol. Results. Data on the primary role of cytochrome CYP2E1 in ethanol metabolism, as well as on the contribution of isoforms CYP1A2, CYP2B1/2, CYP2C, CYP3A4, CYP4B1 to ethanol oxidation are presented. Conclusions. Ethanol is metabolized by many CYPs of endoplasmic reticulum of hepatocytes. The importance of CYP in biotransformation processes in the liver necessitates the study of the role of individual CYP isoforms in ethanol metabolism for predicting changes in the pharmacokinetics of drugs and metabolism of endogenous compounds under the influence of ethanol.
References
Riveros-Rosas H, Julian-Sanchez A, Pinã E. Enzymology of ethanol and acetaldehyde metabolism in mammals. Arch Med Res. 1997;28(4):453-71.
Cederbaum AI. Alcohol metabolism. Clin Liver Dis. 2012;16(4):667-85. https://doi.org/10.1016/j.cld.2012.08.002.
Wilson DF, Matschinsky FM. Ethanol metabolism: The good, the bad, and the ugly. Medical Hypotheses. 2020;140:109638. https://doi.org/10.1016/j.mehy.2020.109638.
Manzo-Avalos S, Saavedra-Molina A. Cellular and mitochondrial effects of alcohol consumption. Int J Environ Res Public Health. 2010;7(12):4281-304. https://doi.org/10.3390/ijerph7124281.
Jones AW. Alcohol, its absorption, distribution, metabolism, and excretion in the body and pharmacokinetic calculations. Wiley Interdisciplinary Reviews Forensic Science. 2019;1(5):e1340. https://doi.org/10.1002/wfs2.1340.
Lieber CS. Ethanol metabolism, cirrhosis and alcoholism. Clin Chim Acta. 1997;257(1):59-84. https://doi.org/10.1016/s0009-8981(96)06434-0.
Hugbart C, Verres Y, Daré BL, Bucher S, Vène E, Bodin A, Lagente V, Fromenty B, Bouvet R, Morel I, Loyer P, Gicquel T. Non-oxidative ethanol metabolism in human hepatic cells in vitro: Involvement of uridine diphospho-glucuronosyltransferase 1A9 in ethylglucuronide production. Toxicol In Vitro. 2020;66:104842. https://doi.org/10.1016/j.tiv.2020.104842.
Heier C, Xie H, Zimmermann R. Nonoxidative ethanol metabolism in humans—from biomarkers to bioactive lipids. IUBMB Life. 2016;68(12):916-923. https://doi.org/10.1002/iub.1569.
Beckemeier ME, Bora PS. Fatty acid ethyl esters: potentially toxic products of myocardial ethanol metabolism. J Mol Cell Cardiol. 1998;30(11):2487-94. https://doi.org/10.1006/jmcc.1998.0812.
Teschke R. Microsomal ethanol-oxidizing system: Success over 50 years and an Encouraging Future. Alcohol Clin Exp Res. 2019;43(3):386-400. https://doi.org/10.1111/acer.13961.
Lieber CS. Metabolism of alcohol. Clin Liver Dis. 2005;9(1):1-35. https://doi.org/10.1016/j.cld.2004.10.005.
Liu J. Ethanol and liver: Recent insights into the mechanisms of ethanol-induced fatty liver. World J Gastroenterol. 2014;20(40):14672-85. https://doi.org/10.3748/wjg.v20.i40.14672.
Lieber CS, DeCarli LM. Ethanol oxidation by hepatic microsomes: Adaptive increase after ethanol feeding. Science. 1968;162(3856):917-8. https://doi.org/10.1126/science.162.3856.917.
Guengerich FP. Cytochrome P450 2E1 and its roles in disease. Chem Biol Interact. 2020;322:109056. https://doi.org/10.1016/j.cbi.2020.109056.
Zimatkin SM, Pronko SP, Vasiliou V, Gonzalez FJ, Deitrich RA. Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res. 2006;30(9):1500-5. https://doi.org/10.1111/j.1530-0277.2006.00181.x.
Lasker JM, Raucy J, Kubota S, Bloswick BP, Black M, Lieber CS. Purification and characterization of human liver cytochrome P-450-ALC. Biochem Biophys Res Commun. 1987;148(1):232-8. https://doi.org/10.1016/0006-291x(87)91100-4.
Lieber CS. Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev. 1997;77(2):517-44. https://doi.org/10.1152/physrev.1997.77.2.517.
Chen J, Jiang S, Wang J, Renukuntla J, Sirimulla S, Chen J. Comprehensive review of cytochrome P450 2E1 for xenobiotic metabolism. Drug Metab Rev. 2019;51(2):178-195. https://doi.org/10.1080/03602532.2019.1632889.
Ingelman-Sundberg M, Johansson I, Yin H, Terelius Y, Eliasson E, Clot P, Albano E. Ethanol-inducible cytochrome P4502E1: Genetic polymorphism, regulation, and possible role in the etiology of alcohol-induced liver disease. Alcohol. 1993;10(6):447-52. https://doi.org/10.1016/0741-8329(93)90063-T.
Kunitoh S, Tanaka T, Imaoka S, Funae Y, Monna Y. Contribution of cytochrome P450s to MEOS (microsomal ethanol-oxidizing system): A specific and sensitive assay of MEOS activity by HPLC with fluorescence labeling. Alcohol Alcohol Suppl. 1993;1B:63-8. https://doi.org/10.1093/alcalc/28.Supplement_1B.63.
Teschke R. Alcoholic liver disease: Alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects. Biomedicines. 2018;6(4):106. https://doi.org/10.3390/biomedicines6040106.
Schoedela KA, Tyndalea RF. Induction of nicotine-metabolizing CYP2B1 by ethanol and ethanol-metabolizing CYP2E1 by nicotine: summary and implications. Biochim Biophys Acta. 2003;1619(3):283-90. https://doi.org/10.1016/s0304-4165(02)00487-7.
Matsumoto H, Matsubayashi K, Fukui Y. Evidence that cytochrome P-4502E1 contributes to ethanol elimination at low doses: effects of diallyl sulfide and 4-methyl pyrazole on ethanol elimination in the perfused rat liver. Alcohol Clin Exp Res. 1996;20(1 Suppl):12A-16A. https://doi.org/10.1111/j.1530-0277.1996.tb01719.x.
Lieber CS. Microsomal ethanol-oxidizing system. Enzyme. 1987;37(1-2):45-56. https://doi.org/10.1159/000469240.
Gonzalez FJ. The 2006 Bernard B. Brodie Award Lecture. Cyp2E1. Drug Metab Dispos. 2007;35(1):1-8. https://doi.org/10.1124/dmd.106.012492.
Jiang Y, Zhang T, Kusumanchi P, Han S, Yang Z, Liangpunsakul S. Alcohol metabolizing enzymes, microsomal ethanol oxidizing system, cytochrome P450 2E1, catalase, and aldehyde dehydrogenase in alcohol-associated liver disease. Biomedicines. 2020;8(3):50. https://doi.org/10.3390/biomedicines8030050.
Takahashi T, Lasker JM, Rosman AS, Lieber CS. Induction of cytochrome P-4502E1 in the human liver by ethanol is caused by a corresponding increase in encoding messenger RNA. Hepatology. 1993;17(2):236-45. https://doi.org/10.1002/hep.1840170213.
Caro AA, Cederbaum AI. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol. 2004;44:27-42. https://doi.org/10.1146/annurev.pharmtox.44.101802.121704.
Tanaka E, Terada M, Misawa S. Cytochrome P450 2E1: its clinical and toxicological role. J Clin Pharm Ther. 2000;25(3):165-75. https://doi.org/10.1046/j.1365-2710.2000.00282.x.
Guengerich FP, Avadhani NG. Roles of cytochrome P450 in metabolism of ethanol and carcinogens. Adv Exp Med Biol. 2018;1032:15-35. https://doi.org/10.1007/978-3-319-98788-0_2.
Knockaert L, Fromenty B, Robin, M-A. Mechanisms of mitochondrial targeting of cytochrome P450 2E1: Physiopathological role in liver injury and obesity. FEBS J. 2011;278(22):4252-60. https://doi.org/10.1111/j.1742-4658.2011.08357.x.
Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med. 2008;44(5):723-38. https://doi.org/10.1016/j.freeradbiomed.2007.11.004.
Aubert J, Begriche K, Knockaert L, Robin MA, Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin Res Hepatol Gastroenterol. 2011;35(10):630-7. https://doi.org/10.1016/j.clinre.2011.04.015.
Millonig G, Wang Y, Homann N, Bernhardt F, Qin H, Mueller S, Bartsch H, Seitz HK. Ethanol-mediated carcinogenesis in the human esophagus implicates CYP2E1 induction and the generation of carcinogenic DNA lesions. Int J Cancer. 2011;128(3):533-40. https://doi.org/10.1002/ijc.25604.
Seitz HK. The role of cytochrome P4502E1 in the pathogenesis of alcoholic liver disease and carcinogenesis. Chem Biol Interact. 2020;316:108918. https://doi.org/10.1007/s00394-020-02421-y.
Lu Y, Cederbaum AI. Cytochrome P450s and alcoholic liver disease. Curr Pharm Des. 2018;24(14):1502-1517. https://doi.org/10.2174/1381612824666180410091511.
Leung TM, Lu Y. Alcoholic liver disease: from CYP2E1 to CYP2A5. Curr Mol Pharmacol. 2017;10(3):172-178. https://doi.org/10.2174/1874467208666150817111846.
Rendic SP, Guengerich FP. Human Family 1-4 cytochrome P450 enzymes involved in the metabolic activation of xenobiotic and physiological chemicals: an update. Arch Toxicol. 2021;95(2):395-472. https://doi.org/10.1007/s00204-020-02971-4.
Hamitouche S, Poupon J, Dreano Y, Amet Y, Lucas D. Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: Role of CYP2C isoforms in human liver microsomes. Toxicol Lett. 2006;167(3):221-30. https://doi.org/10.1016/j.toxlet.2006.09.011.
Kunitoh S, Asai H, Imaoka S, Funae Y, Monna T. Metabolism of acetaldehyde to acetate by rat hepatic P-450s: presence of different metabolic pathway from acetaldehyde dehydrogenase system. Alcohol Clin Exp Res. 1996;20(1 Suppl):22A-24A. https://doi.org/10.1111/j.1530-0277.1996.tb01721.x.
Asai H, Imaoka S, Kurolu T, Monna T, Funae Y. Microsomal ethanol oxidizing system activity by human hepatic cytochrome P450s. J Pharmacol Exp Ther. 1996;277(2):1004-9.
Guengerich FP. Cytochromes P450, drugs, and diseases. Mol Interv. 2003;3(4):194-204. https://doi.org/10.1124/mi.3.4.194.
Salmela KS, Kessova IG, Tsyrlov IB, Lieber CS. Respective roles of human cytochromes P-4502E1, 1A2, and 3A4 in the hepatic microsomal ethanol oxidizing system. Alcohol Clin Exp Res. 1998;22(9):2125-32. https://doi.org/10.1111/j.1530-0277.1998.tb05926.x.
Gerbal-Chaloin S, Pascussi JM, Pichard-Garcia L, Daujat M, Waechter F, Fabre JM, Carrere N, Maurel P, 2001. Induction of CYP2C genes in human hepatocytes in primary culture. Drug Metab Dispos. 2001;29(3):242-51.
Kim Y-D, Oyama T, Isse T, Kim H, Kawamoto T. Expression levels of hepatic cytochrome P450 enzymes in Aldh2-deficient mice following ethanol exposure: a pilot study. Arch Toxicol. 2005;79(4):192-5. https://doi.org/10.1007/s00204-004-0630-8.
Novak RF, Woodcroft KJ. The alcohol-inducible form of cytochrome P450 (CYP 2E1): role in toxicology and regulation of expression. Arch Pharm Res. 2000;23(4):267-82. https://doi.org/10.1007/BF02975435.
Sutsko IP. Vlijanie 5-formiltetragidrofolievoj kisloty na harakter izmenenija aktivnosti citohrom P450-zavisimoj monooksigenaznoj sistemy gepatocitov i nekotorye biohimicheskie pokazateli krovi krys pri hronicheskoj alkogolnoj intoksikacii [Effect of 5-formyltetrahydrofolic acid on the activity of the cytochrome P450-dependent monooxygenase system of hepatocytes and some biochemical parameters of the blood of rats with chronic alcohol intoxication]. Zhurnal Grodnenskogo gosudarstvennogo medicinskogo universiteta [Journal of the Grodno State Medical University]. 2011;1(33):49-52. http://elib.grsmu.by/handle/files/5967. (Russian).
Nebert DW, Wikvall K, Miller WL. Human cytochromes P450 in health and disease. Philos Trans R Soc Lond B Biol Sci. 2013;368(1612):20120431. https://doi.org/10.1098/rstb.2012.0431.
Pikuleva IA, Waterman MR. Cytochromes P450: Roles in diseases. J Biol Chem. 2013;288(24):17091-8. https://doi.org/10.1074/jbc.R112.431916.
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