细胞色素P450 3A4 代谢机制有关方面的研究进展

摘要/Abstract

摘要： YP3A4是细胞色素P450 家族中最为重要的药物代谢酶,其在外源性物质和内源性物质的代谢中起着极其重要的作用。本文通过查阅国内外相关文献,对CYP3A4的基本结构、活性部位、作用机制、基因表型、探针底物和药物代谢等方面的研究进展作一综述,从而阐明CYP3A4与代谢机制有关的问题。

关键词: CYP3A4, 基因多态性, 作用机制, 药物代谢, 探针底物

Abstract: The cytochrome P450 (CYP) enzymes, involved in the metabolism of therapeutic drugs, are the major determinants of drug half-life. Among 57 human P450s, CYP3A4 is the most abundant and the most important because it metabolizes the majority of administered drugs. In this review we provide an overview on recent progress in the CYP3A4 research, such as basic structure, active site, mechanism of action, genetic phenotypes, probe substrate, drug metabolism and so on.

Key words: CYP3A4, gene polymorphism, mechanism of action, metabolism, probe

中图分类号:

R969.1

黄伟, 胡晓. 细胞色素P450 3A4 代谢机制有关方面的研究进展[J]. 中国临床药理学与治疗学, 2015, 20(2): 223-229.

HUANG Wei, HU Xiao. Study on the mechanism of cytochrome P450 3A4[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(2): 223-229.

参考文献

[1] Guengerich FP, Wu ZL, Bartleson CJ. Function of human cytochrome P450s: characterization of the orphans[J]. Biochem Biophys Res Commun,2005, 338(1):465-469.
[2] Nelson DR, Nebert DW. Cytochrome P450 (CYP) gene superfamily[J]. eLS, 2011,17(1):258-261.
[3] 黄路, 阳国平. CYP450 氧化还原酶遗传多态性对 CYP 酶影响的研究进展[J]. 中国临床药理学与治疗学, 2013, 18(7):818-823.
[4] Nebert DW, Russell DW. Clinical importance of the cytochromes P450[J]. Lancet, 2002, 360(9340):1155-1162.
[5] Atkins WM. Non-Michaelis-Menten kinetics in cytochrome P450-catalyzed reactions[J]. Annu Rev Pharmacol Toxicol, 2005, 45(2):291-310.
[6] Denisov IG, Frank DJ, Sligar SG, et al. Cooperative properties of cytochromes P450[J]. Pharmacol Ther, 2009, 124(2):151-167.
[7] Denisov IG, Sligar SG. A novel type of allosteric regulation: Functional cooperativity in monomeric proteins[J]. Arch Biochem Biophys, 2012, 519(2):91-102.
[8] Niwa T, Murayama N, Yamazaki H, et al. Heterotropic cooperativity in oxidation mediated by cytochrome P450[J]. Curr Drug Metab, 2008, 9(5):453-462.
[9] Sligar SG, Denisov IG. Understanding cooperativity in human P450 mediated drug-drug interactions[J]. Drug Metab Rev, 2007, 39(2/3):567-579.
[10]本报特约撰稿人. CYP3A4晶体结构揭晓[J]. 医药经济报. 2004-09-03.
[11]Sevrioukova IF, Poulos TL. Understanding the mechanism of cytochrome P450 3A4: recent advances and remaining problems[J]. Dalton Trans, 2013, 42(9):3116-3126.
[12]Fowler SM, Riley RJ, Pritchard MP, et al. Amino acid 305 determines catalytic center accessibility in CYP3A4[J]. Biochemistry, 2000, 39(15):4406-4414.
[13]Fowler SM, Taylor JM, Friedberg T, et al. CYP3A4 active site volume modification by mutagenesis of leucine 211[J]. Drug Metab Dispos, 2002, 30(4):452-456.
[14]Khan KK, He YQ, Domanski TL, et al. Midazolam oxidation by cytochrome P450 3A4 and active-site mutants: an evaluation of multiple binding sites and of the metabolic pathway that leads to enzyme inactivation[J]. Mol Pharmacol, 2002, 61(3):495-506.
[15]Farooq Y, Roberts G. Kinetics of electron transfer between NADPH-cytochrome P450 reductase and cytochrome P450 3A4[J]. Biochem J, 2010, 432(3):485-493.
[16]He YA, Roussel F, Halpert JR. Analysis of homotropic and heterotropic cooperativity of diazepam oxidation by CYP3A4 using site-directed mutagenesis and kinetic modeling[J]. Arch Biochem Biophys, 2003, 409(1):92-101.
[17]Baas BJ, Denisov IG, Sligar SG. Homotropic cooperativity of monomeric cytochrome P450 3A4 in a nanoscale native bilayer environment[J]. Arch Biochem Biophys, 2004, 430(2):218-228.
[18]Denisov IG, Baas BJ, Grinkova YV, et al. Cooperativity in cytochrome P450 3A4 linkages in substrate binding, spin state, uncoupling, and product formation[J]. J Biol Chem, 2007, 282(10):7066-7076.
[19]Ma H, Fu T, Li G: Computational studies on drug-drug Interactions and Drug-metabolism Enzyme Interactions, Drug Metab Rev, informa healthcare telephone house, 69-77 paul street, london ec2a 4lq, england, 2011, 43: 62-63.
[20]Roberts AG, Yang J, Halpert JR, et al. The structural basis for homotropic and heterotropic cooperativity of midazolam metabolism by human cytochrome P450 3A4[J]. Biochemistry, 2011, 50(50):10804-10818.
[21]Sevrioukova IF, Poulos TL. Understanding the mechanism of cytochrome P450 3A4: recent advances and remaining problems[J]. Dalton Trans, 2013, 42(9):3116-3126.
[22]Evans WE, Relling MV. Pharmagenomics: translating functional genomics into rational therapeutics[J].Science, 1999, 286(5439):487- 491.
[23]Hsieh KP, Lin YY, Cheng CL, et al. Novel mutations of CYP3A4 in Chinese[J]. Drug Metab Dispos, 2001, 29(3):268-273.
[24]Lewis DF, Pratt JM. The P450 catalytic cycle and oxygenation mechanism[J]. Drug Metab Rev, 1998, 30(4):739-786.
[25]Rebbeck TR, Jaffe JM, Walker AH, et al. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4[J]. J Natl Cancer Inst,1998, 90(16): 1225-1229.
[26]Collado M, Barragan E, Bolufer P, et al.Lack of association ofCYP3A4-V polymorphism with the risk of treatment-related leukemia[J]. Leuk Res,2005, 29(5): 595-597.
[27]Jing Du, Qinghe Xing, Lingyun Xu, et al. Systematic screening for polymorphisms in the CYP3A4 gene in the Chinese population[J]. Pharmacogenomics, 2006, 7( 6): 831-841.
[28]Sata F, Sapone A, Elizondo G, et al. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity[J]. Clin Pharmacol Ther, 2000, 67(1):48-56.
[29]李纳, 施孝金. 细胞色素P450酶基因多态性的研究进展及临床意义[J]. 中国临床药理学与治疗学, 2009(10):1193-1200.
[30]Dai D, Tang J, Rose R, et al. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos[J]. J Pharmacol Exp Ther,2001, 299(3):825-831.
[31]Wang A,Yu BN,Luo CH,et al. IIe118Val genetic polymorphism of CYP3A4 and its effects on lipid-lowering efficacy of simvastatin in Chinese hyperlipidemic patients[J]. Eur J Clin Pharmacol, 2005,60(12):843-848.
[32]Rodriguez-Antona C,Sayi JG,Gustafsson LL,et al. Pheno-type-genotype variability in the human CYP3A locus as as-sessed by the probe drug quinine and analyses of variant CYP3A4 alleles[J]. Biochem Biophys Res Commum, 2005,338(1):299-305.
[33]何霞, 童荣生. CYP3A4和CYP3A5基因多态性对汉族肾移植患者他克莫司血药浓度的影响[J]. 中国药师, 2013, 16(4): 497-501.
[34]Gao Y,Zhang LR,Fu Q.CYP3A4*1G polymorphism is associated with lipid-lowering efficacy of atorbvastatin but not of simvastatin[J]. Eur J Clin Pharmacol, 2008,64(9):877-882.
[35]戴春岭, 李苏, 梁永钜, 等. 建立一种测定细胞色素 P450 3A4 活性的方法[J]. 中国药学杂志, 2006, 41(18):1420-1423.
[36]Kenworthy K, Bloomer J, Clarke S, et al. CYP3A4 drug interactions: correlation of 10 in vitro probe substrates[J]. British journal of clinical pharmacology, 1999, 48(5):716-727.
[37]Yuan R, Madani S, Wei XX, et al. Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions[J]. Drug Metab Dispos, 2002, 30(12):1311-1319.
[38]Weaver R, Graham KS, Beattie IG, et al. Cytochrome P450 inhibition using recombinant proteins and mass spectrometry/multiple reaction monitoring technology in a cassette incubation[J]. Drug Metab Dispos, 2003, 31(7):955-966.
[39]Huang W, Lin YS, McConn DJ, et al. Evidence of significant contribution from CYP3A5 to hepatic drug metabolism[J]. Drug Metab Dispos,2004, 32(12):1434-1445.
[40]Ekroos M, Sjögren T. Structural basis for ligand promiscuity in cytochrome P450 3A4[J]. Proc Natl Acad Sci U S A, 2006, 103(37):13682-13687.
[41]McGinnity DF, Parker AJ, Soars M, et al. Automated definition of the enzymology of drug oxidation by the major human drug metabolizing cytochrome P450s[J]. Drug Metab Dispos, 2000, 28(11):1327-1334.
[42]Mirghani RA, Yasar Ü, Zheng T, et al. Enzyme kinetics for the formation of 3-hydroxyquinine and three new metabolites of quinine in vitro; 3-hydroxylation by CYP3A4 is indeed the major metabolic pathway[J]. Drug Metab Dispos, 2002, 30(12):1368-1371.
[43]边婷: 人肝脏 CYP3A4 在 mRNA 和蛋白质表达及硝苯地平氧化反应速率上的关联分析[D]. 西北大学, 2011.
[44]Stresser DM, Blanchard AP, Turner SD, et al. Substrate-dependent modulation of CYP3A4 catalytic activity: analysis of 27 test compounds with four fluorometric substrates[J]. Drug Metab Dispos, 2000, 28(12):1440-1448.
[45]Jerling M, Dahl ML, Åberg-Wistedt A, et al. The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol&ast[J]. Clin Pharmacol Ther,1996, 59(4):423-428.
[46]姜敏, 熊玉卿. 细胞色素氧化酶 P4503A4与药物代谢[J]. 实用临床医学, 2006, 7(11):199-201.
[47]周权,姚彤炜,曾苏.代谢性药物相互作用[J].中国临床药理学杂志,2001,17(4) :313-318.