细胞色素P450家族在肝脏代谢相关疾病中的作用

陈玮钰; 舒发明; 王涵; 曹杨港; 胡锦; 毛德文

doi:10.3969/j.issn.1001-5256.2022.09.045

细胞色素P450家族在肝脏代谢相关疾病中的作用

DOI: 10.3969/j.issn.1001-5256.2022.09.045

陈玮钰¹,
舒发明²,
王涵¹,
曹杨港¹,
胡锦¹,
毛德文^2, , ,

1.
广西中医药大学研究生院，南宁 530001
2.
广西中医药大学第一附属医院肝病科，南宁 530023

基金项目:

国家自然科学基金 (81960841);

国家自然科学基金 (82060848);

广西自然科学基金创新研究团队项目 (2018GXNSFGA281002);

广西壮族自治区中青年教师科研基础能力提升项目 (2019KY0336)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：陈玮钰负责拟定写作思路并撰写文章；王涵参与相关文献的收集与整理；曹杨港、胡锦负责整理数据；毛德文、舒发明提供指导意见并修改论文。

详细信息

通信作者:
毛德文，mdwboshi2005@163.com

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出版历程
- 收稿日期: 2022-03-12
- 录用日期: 2022-04-13
- 出版日期: 2022-09-20

Role of the cytochrome P450 family in metabolic-associated liver diseases

1.
Graduate School of Guangxi University of Chinese Medicine, Nanning 530001, China
2.
Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China

Research funding:

National Natural Science Foundation of China (81960841);

National Natural Science Foundation of China (82060848);

Guangxi Natural Science Foundation Innovation Research Team Project (2018GXNSFGA281002);

Project for Improving Young and Middle-Aged Teachers' Basic Scientific Research Ability in Guangxi Zhuang Autonomous Region (2019KY0336)

More Information

Corresponding author: MAO Dewen, mdwboshi2005@163.com(ORCID: 0000-0001-9438-9325)

摘要

摘要: 细胞色素P450(CYP)家族是体内最重要的药物代谢酶，负责内源性和外源性化合物的代谢。肝脏作为CYP家族表达的主要部位，是药物的代谢中心。近年来，CYP家族在肝脏中的作用受到国内外学者的广泛关注。本文就CYP家族在解剖学、遗传学、基因组学等方面的分布差异，以及在非酒精性脂肪性肝病、酒精性肝病、肝纤维化、肝硬化、肝细胞癌等病理过程中的表达变化作一综述，深入探讨CYP家族介导的酶活性对肝脏代谢相关疾病药物治疗效果的影响，以期为寻找疾病中关键的药物干预靶点和增强临床疗效及安全性提供重要启示。
- 肝疾病 /
- 细胞色素P450酶系统 /
- 药代动力学
Abstract: The cytochrome P450 (CYP) family is the most important drug-metabolizing enzyme in human body and is responsible for the metabolism of endogenous and exogenous compounds. As the main site of the expression of the CYP family, the liver is the metabolic center of drugs, and in recent years, the role of the CYP family in the liver has attracted wide attention from the scholars in China and globally. This article reviews the distribution differences of the CYP family from the aspects of anatomy, genetics, and genomics, changes in the expression of the CYP family in the pathological processes such as non-alcoholic fatty liver disease, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma, and the effect of CYP family-mediated enzyme activity on the treatment effect of pharmacotherapy for metabolic-associated liver diseases, in order to provide important enlightenment for identifying key drug intervention targets in diseases and enhancing clinical efficacy and safety.
- Liver Diseases /
- Cytochrome P-450 Enzyme System /
- Pharmacokinetics

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参考文献(49)

[1]	OMURA T, SATO R. A new cytochrome in liver microsomes[J]. J Biol Chem, 1962, 237(4): 1375-1376.
[2]	BACHMANN KA, LEWIS JD. Predicting inhibitory drug-drug interactions and evaluating drug interaction reports using inhibition constants[J]. Ann Pharmacother, 2005, 39(6): 1064-1072. DOI: 10.1345/aph.1E508.
[3]	RENDIC S, GUENGERICH FP. Survey of human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals[J]. Chem Res Toxicol, 2015, 28(1): 38-42. DOI: 10.1021/tx500444e.
[4]	AKIYAMA S, SAKU N, MIYATA S, et al. Drug metabolic activity is a critical cell-intrinsic determinant for selection of hepatocytes during long-term culture[J]. Stem Cell Res Ther, 2022, 13(1): 104. DOI: 10.1186/s13287-022-02776-5.
[5]	ALMAZROO OA, MIAH MK, VENKATARAMANAN R. Drug metabolism in the liver[J]. Clin Liver Dis, 2017, 21(1): 1-20. DOI: 10.1016/j.cld.2016.08.001.
[6]	ZHAO M, MA J, LI M, et al. Cytochrome P450 enzymes and drug metabolism in humans[J]. Int J Mol Sci, 2021, 22(23): 12808. DOI: 10.3390/ijms222312808.
[7]	TRENAMAN SC, BOWLES SK, ANDREW MK, et al. The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs[J]. Pharmacol Res Perspect, 2021, 9(3): e00775. DOI: 10.1002/prp2.775.
[8]	STEYN SJ, VARMA M. Cytochrome-P450-mediated drug-drug interactions of substrate drugs: Assessing clinical risk based on molecular properties and an extended clearance classification system[J]. Mol Pharm, 2020, 17(8): 3024-3032. DOI: 10.1021/acs.molpharmaceut.0c00444.
[9]	KATO H. Computational prediction of cytochrome P450 inhibition and induction[J]. Drug Metab Pharmacokinet, 2020, 35(1): 30-44. DOI: 10.1016/j.dmpk.2019.11.006.
[10]	ALBERTOLLE ME, PHAN T, POZZI A, et al. Sulfenylation of human liver and kidney microsomal cytochromes P450 and other drug-metabolizing enzymes as a response to redox alteration[J]. Mol Cell Proteomics, 2018, 17(5): 889-900. DOI: 10.1074/mcp.RA117.000382.
[11]	SONG Y, LI C, LIU G, et al. Drug-metabolizing cytochrome P450 enzymes have multifarious influences on treatment outcomes[J]. Clin Pharmacokinet, 2021, 60(5): 585-601. DOI: 10.1007/s40262-021-01001-5.
[12]	GASTELUM G, JIANG W, WANG L, et al. Polycyclic aromatic hydrocarbon-induced pulmonary carcinogenesis in cytochrome P450 (CYP)1A1- and 1A2-null mice: Roles of CYP1A1 and CYP1A2[J]. Toxicol Sci, 2020, 177(2): 347-361. DOI: 10.1093/toxsci/kfaa107.
[13]	ZANGER UM, SCHWAB M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation[J]. Pharmacol Ther, 2013, 138(1): 103-141. DOI: 10.1016/j.pharmthera.2012.12.007.
[14]	MARCOS-VADILLO E, CARRASCAL-LASO L, RAMOS-GALLEGO I, et al. Case report: Pharmacogenetics applied to precision psychiatry could explain the outcome of a patient with a new CYP2D6 genotype[J]. Front Psychiatry, 2021, 12: 830608. DOI: 10.3389/fpsyt.2021.830608.
[15]	ZHANG HF, WANG HH, GAO N, et al. Physiological content and intrinsic activities of 10 cytochrome P450 isoforms in human normal liver microsomes[J]. J Pharmacol Exp Ther, 2016, 358(1): 83-93. DOI: 10.1124/jpet.116.233635.
[16]	PALMER CN, COATES PJ, DAVIES SE, et al. Localization of cytochrome P-450 gene expression in normal and diseased human liver by in situ hybridization of wax-embedded archival material[J]. Hepatology, 1992, 16(3): 682-687. DOI: 10.1002/hep.1840160311.
[17]	RODRÍGUEZ-ANTONA C, DONATO MT, PAREJA E, et al. Cytochrome P-450 mRNA expression in human liver and its relationship with enzyme activity[J]. Arch Biochem Biophys, 2001, 393(2): 308-315. DOI: 10.1006/abbi.2001.2499.
[18]	YANG X, ZHANG B, MOLONY C, et al. Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver[J]. Genome Res, 2010, 20(8): 1020-1036. DOI: 10.1101/gr.103341.109.
[19]	LIU J, LU YF, CORTON JC, et al. Expression of cytochrome P450 isozyme transcripts and activities in human livers[J]. Xenobiotica, 2021, 51(3): 279-286. DOI: 10.1080/00498254.2020.1867929.
[20]	FANNI D, PINNA F, GEROSA C, et al. Anatomical distribution and expression of CYP in humans: Neuropharmacological implications[J]. Drug Dev Res, 2021, 82(5): 628-667. DOI: 10.1002/ddr.21778.
[21]	ZHANG HF, ZHU LL, YANG XB, et al. Variation in the expression of cytochrome P450-related miRNAs and transcriptional factors in human livers: Correlation with cytochrome P450 gene phenotypes[J]. Toxicol Appl Pharmacol, 2021, 412: 115389. DOI: 10.1016/j.taap.2020.115389.
[22]	STIPP MC, ACCO A. Involvement of cytochrome P450 enzymes in inflammation and cancer: a review[J]. Cancer Chemother Pharmacol, 2021, 87(3): 295-309. DOI: 10.1007/s00280-020-04181-2.
[23]	LEONI S, TOVOLI F, NAPOLI L, et al. Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis[J]. World J Gastroenterol, 2018, 24(30): 3361-3373. DOI: 10.3748/wjg.v24.i30.3361.
[24]	JAMWAL R, BARLOCK BJ. Nonalcoholic fatty liver disease (NAFLD) and hepatic cytochrome P450 (CYP) enzymes[J]. Pharmaceuticals (Basel), 2020, 13(9): 222. DOI: 10.3390/ph13090222.
[25]	STEPHENSON K, KENNEDY L, HARGROVE L, et al. Updates on dietary models of nonalcoholic fatty liver disease: Current studies and insights[J]. Gene Expr, 2018, 18(1): 5-17. DOI: 10.3727/105221617X15093707969658.
[26]	ANAVI S, MADAR Z, TIROSH O. Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers[J]. Redox Biol, 2017, 13: 386-392. DOI: 10.1016/j.redox.2017.06.008.
[27]	KROGSTAD V, PERIC A, ROBERTSEN I, et al. Correlation of body weight and composition with hepatic activities of cytochrome P450 enzymes[J]. J Pharm Sci, 2021, 110(1): 432-437. DOI: 10.1016/j.xphs.2020.10.027.
[28]	WOOLSEY SJ, MANSELL SE, KIM RB, et al. CYP3A activity and expression in nonalcoholic fatty liver disease[J]. Drug Metab Dispos, 2015, 43(10): 1484-1490. DOI: 10.1124/dmd.115.065979.
[29]	OHASHI K, PIMIENTA M, SEKI E. Alcoholic liver disease: A current molecular and clinical perspective[J]. Liver Res, 2018, 2(4): 161-172. DOI: 10.1016/j.livres.2018.11.002.
[30]	HARTMANN P, HOCHRATH K, HORVATH A, et al. Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice[J]. Hepatology, 2018, 67(6): 2150-2166. DOI: 10.1002/hep.29676.
[31]	HYUN J, HAN J, LEE C, et al. Pathophysiological aspects of alcohol metabolism in the liver[J]. Int J Mol Sci, 2021, 22(11): 5717. DOI: 10.3390/ijms22115717.
[32]	LIEBER CS. Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis[J]. Alcohol, 2004, 34(1): 9-19. DOI: 10.1016/j.alcohol.2004.07.008.
[33]	LU Y, ZHUGE J, WANG X, et al. Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice[J]. Hepatology, 2008, 47(5): 1483-1494. DOI: 10.1002/hep.22222.
[34]	LU Y, WU D, WANG X, et al. Chronic alcohol-induced liver injury and oxidant stress are decreased in cytochrome P4502E1 knockout mice and restored in humanized cytochrome P4502E1 knock-in mice[J]. Free Radic Biol Med, 2010, 49(9): 1406-1416. DOI: 10.1016/j.freeradbiomed.2010.07.026.
[35]	LU Y, CEDERBAUM AI. Cytochrome P450s and alcoholic liver disease[J]. Curr Pharm Des, 2018, 24(14): 1502-1517. DOI: 10.2174/1381612824666180410091511.
[36]	CHO YE, KIM DK, SEO W, et al. Fructose promotes leaky gut, endotoxemia, and liver fibrosis through ethanol-inducible cytochrome P450-2E1-mediated oxidative and nitrative stress[J]. Hepatology, 2021, 73(6): 2180-2195. DOI: 10.1002/hep.30652.
[37]	WELTMAN MD, FARRELL GC, HALL P, et al. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis[J]. Hepatology, 1998, 27(1): 128-133. DOI: 10.1002/hep.510270121.
[38]	HONG F, SI C, GAO P, et al. The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference[J]. Naunyn Schmiedebergs Arch Pharmacol, 2016, 389(1): 33-43. DOI: 10.1007/s00210-015-1172-8.
[39]	MUHSAIN SN, LANG MA, ABU-BAKAR A. Mitochondrial targeting of bilirubin regulatory enzymes: An adaptive response to oxidative stress[J]. Toxicol Appl Pharmacol, 2015, 282(1): 77-89. DOI: 10.1016/j.taap.2014.11.010.
[40]	ELBEKAI RH, KORASHY HM, EL-KADI AO. The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes[J]. Curr Drug Metab, 2004, 5(2): 157-167. DOI: 10.2174/1389200043489054.
[41]	VAVILIN VA, NEPOMNYASHCHIKH DL, SHCHEPOTINA EG, et al. Cytochrome P450 4F2 polymorphism in patients with liver cirrhosis[J]. Bull Exp Biol Med, 2013, 156(2): 181-184. DOI: 10.1007/s10517-013-2305-z.
[42]	XIE Y, WANG G, WANG H, et al. Cytochrome P450 dysregulations in thioacetamide-induced liver cirrhosis in rats and the counteracting effects of hepatoprotective agents[J]. Drug Metab Dispos, 2012, 40(4): 796-802. DOI: 10.1124/dmd.111.043539.
[43]	NEPOMNYASHCHIKH DL, VAVILIN VA, AIDAGULOVA SV, et al. Cytochrome P450 2D6 polymorphism is a molecular genetic marker of liver cirrhosis progression[J]. Bull Exp Biol Med, 2012, 152(5): 633-636. DOI: 10.1007/s10517-012-1595-x.
[44]	SIEGEL RL, MILLER KD, FUCHS HE, et al. Cancer Statistics, 2021[J]. CA Cancer J Clin, 2021, 71(1): 7-33. DOI: 10.3322/caac.21654.
[45]	NEKVINDOVA J, MRKVICOVA A, ZUBANOVA V, et al. Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450[J]. Biochem Pharmacol, 2020, 177: 113912. DOI: 10.1016/j.bcp.2020.113912.
[46]	JIANG T, ZHU AS, YANG CQ, et al. Cytochrome P450 2A6 is associated with macrophage polarization and is a potential biomarker for hepatocellular carcinoma[J]. FEBS Open Bio, 2021, 11(3): 670-683. DOI: 10.1002/2211-5463.13089.
[47]	CHEN L, BAO Y, PIEKOS SC, et al. A transcriptional regulatory network containing nuclear receptors and long noncoding RNAs controls basal and drug-induced expression of cytochrome P450s in HepaRG cells[J]. Mol Pharmacol, 2018, 94(1): 749-759. DOI: 10.1124/mol.118.112235.
[48]	LI X, LI S, WANG B, et al. Borneol influences the pharmacokinetics of florfenicol through regulation of cytochrome P450 1A2 (CYP1A2), CYP2C11, CYP3A1, and multidrug resistance 1 (MDR1) mRNA expression levels in rats[J]. J Vet Med Sci, 2021, 83(8): 1338-1344. DOI: 10.1292/jvms.20-0641.
[49]	QI Y, TOYOOKA T, HORIGUCHI H, et al. 2-mercaptobenzothiazole generates γ-H2AX via CYP2E1-dependent production of reactive oxygen species in urothelial cells[J]. J Biochem Mol Toxicol, 2022. DOI: 10.1002/jbt.23043. [Online ahead of print]