РОЛЬ ИЗОФОРМ ЦИТОХРОМА Р450 ЭНДОПЛАЗМАТИЧЕСКОГО РЕТИКУЛУМА ГЕПАТОЦИТОВ В МЕТАБОЛИЗМЕ ЭТАНОЛА
Аннотация
Введение. Известно, что системное окисление этанола в печени включает три метаболических пути, которые могут функционировать параллельно: с участием алкогольдегидрогеназ, ферментов микросомального окисления и каталазы пероксисом. Цитохром Р450-зависимая микросомальная этанолокисляющая система играет незначительную роль в метаболизме небольших количеств этанола, но индуцируется при его избытке и приобретает существенное значение при злоупотреблении им. Основные компоненты данной системы – изоформы цитохрома Р450 (CYP) гладкой эндоплазматической сети. Цель исследования. Охарактеризовать роль ключевых изоформ цитохрома Р450 в окисление этанола. Материал и методы. Проведен анализ современных литературных данных об участии основных изоформ цитохрома Р450 в метаболизме этанола в печени. Результаты. Представлены данные о первостепенной роли в метаболизме этанола цитохрома CYP2E1, а также вкладе в окисление этанола изоформ CYP1А2, CYP2В1/2, CYP2C, CYP3А4, CYP4B1. Выводы. Этанол метаболизируется многими CYP эндоплазматического ретикулума гепатоцитов. Учитывая важную роль CYP в процессах биотрансформации в печени, изучение роли отдельных изоформ CYP в метаболизме этанола имеет значение для прогнозирования изменения фармакокинетики лекарственных средств и метаболизма эндогенных соединений под воздействием этанола.
Литература
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.
