细胞色素P450氧化酶的遗传变异与个体化药物治疗

中国临床药理学与治疗学 ›› 2014, Vol. 19 ›› Issue (11): 1281-1287.

细胞色素P450氧化酶的遗传变异与个体化药物治疗

吕佩瑜¹, 袁洪³, 周宏灏^{1, 2}, 欧阳冬生^{1, 2}

¹ 中南大学湘雅医院临床药理研究所,
² 中南大学临床药理研究所,长沙 410078,湖南
³ 中南大学湘雅三医院临床药理研究中心,长沙 410013,湖南

收稿日期:2014-04-21 修回日期:2014-05-21 出版日期:2014-11-26 发布日期:2014-12-09
作者简介:吕佩瑜,女,硕士,研究方向:遗传药理学与药物基因组学。 Tel: 18229871627 E-mail: lvpeiyu1988@163.com。欧阳冬生,男,博士,博导,研究方向:遗传药理学与药物基因组学,临床药理学。 Tel: 0731-84808380 E-mail: ouyangyj@163.com
基金资助:
国家重大新药创制“十二五”实施计划(2012ZX09303014-001)

Genetic variation of cytochrome P450 oxidase and personalized medicine

LV Pei-yu¹, YUAN Hong³, ZHOU Hong-hao^{1, 2}, OUYANG Dong-sheng^{1, 2}

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University;
² Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan,China;
³ Center of Clinical Pharmacology of the Third Xiangya Hospital of Central South University, Changsha 410013, Hunan,China

Received:2014-04-21 Revised:2014-05-21 Online:2014-11-26 Published:2014-12-09

摘要/Abstract

摘要： 细胞色素P450氧化酶的基因多态性是导致药物代谢个体差异的重要原因。已经发现的数百万个基因突变中,仅有少数影响蛋白功能,极少部分具有临床意义。本文综述了功能相关的细胞色素P450氧化酶的基因多态性的研究进展,以期为个体化药物治疗提供参考。

关键词: 细胞色素P450氧化酶, 基因多态性, 药物代谢, 个体化治疗

Abstract: Genetic polymorphisms of cytochrome P450 oxidase is an important cause of individual differences in drug metabolism. Only very few of the reported mutations are functional. We review the research progress of mechanized functionally related gene polymorphisms of cytochrome P450 oxidase to provide a reference for drug individualized treatment.

Key words: cytochrome P450 oxidase, gene polymorphism, drug metabolism, personalized medicine

中图分类号:

R969.8

吕佩瑜, 袁洪, 周宏灏, 欧阳冬生. 细胞色素P450氧化酶的遗传变异与个体化药物治疗[J]. 中国临床药理学与治疗学, 2014, 19(11): 1281-1287.

LV Pei-yu, YUAN Hong, ZHOU Hong-hao, OUYANG Dong-sheng. Genetic variation of cytochrome P450 oxidase and personalized medicine[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(11): 1281-1287.

参考文献 36

[1]	李晓宇, 刘皋林. CYP450酶特性及其应用研究进展[J]. 中国临床药理学与治疗学, 2008, 13(8): 942-946.
[2]	Lee SJ, Goldstein JA.Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests[J]. Pharmacogenomics, 2005, 6(4): 357-371.
[3]	Zochowska D, Wyzgal J, Paczek L.Impact of CYP3A41B and CYP3A53 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients[J]. Ann Transplant, 2012, 17(3): 36-44.
[4]	Lamba J, Hebert JM, Schuetz EG, et al.PharmGKB summary: very important pharmacogene information for CYP3A5[J]. Pharmacogenet Genomics, 2012, 22(7): 555-558.
[5]	Zuo X, Zhang W, Yuan H, et al.ABCB1 polymorphism and gender affect the pharmacokinetics of amlodipine in Chinese patients with essential hypertension: a population analysis[J]. Drug Metab Pharmacokinet, 2014,29(4):305-311.
[6]	Surendiran A, Pradhan SC, Agrawal A, et al.Influence of CYP2C9 gene polymorphisms on response to glibenclamide in type 2 diabetes mellitus patients[J]. Eur J Clin Pharmacol, 2011, 67(8): 797-801.
[7]	Xie HG, Prasad HC, Kim RB, et al.CYP2C9 allelic variants: ethnic distribution and functional significance[J]. Adv Drug Deliv Rev, 2002, 54(10): 1257-1270.
[8]	Garcia-Martin E, Martinez C, Tabares B, et al.Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms[J]. Clin Pharmacol Ther, 2004, 76(2): 119-127.
[9]	Sim SC, Risinger C, Dahl ML, et al.A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants[J]. Clin Pharmacol Ther, 2006, 79(1): 103-113.
[10]	Huezo-Diaz P, Perroud N, Spencer EP, et al.CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP[J]. J Psychopharmacol, 2012, 26(3): 398-407.
[11]	Andersson T, Flockhart DA, Goldstein DB, et al.Drug-metabolizing enzymes: evidence for clinical utility of pharmacogenomic tests[J]. Clin Pharmacol Ther, 2005, 78(6): 559-581.
[12]	Raimundo S, Toscano C, Klein K, et al.A novel intronic mutation, 2988G> A, with high predictivity for impaired function of cytochrome P450 2D6 in white subjects[J]. Clin Pharmacol Ther, 2004, 76(2): 128-138.
[13]	Toscano C, Klein K, Blievernicht J, et al.Impaired expression of CYP2D6 in intermediate metabolizers carrying the *41 allele caused by the intronic SNP 2988G>A: evidence for modulation of splicing events[J]. Pharmacogenet Genomics, 2006, 16(10): 755-766.
[14]	Ghotbi R, Christensen M, Roh HK, et al.Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans[J]. Eur J Clin Pharmacol, 2007, 63(6): 537-546.
[15]	Zhou H, Josephy PD, Kim D, et al.Functional characterization of four allelic variants of human cytochrome P450 1A2[J]. Arch Biochem Biophys, 2004, 422(1): 23-30.
[16]	Ingelman-Sundberg M, Sim SC, Gomez A, et al.Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects[J]. Pharmacol Ther, 2007, 116(3): 496-526.
[17]	Di Iulio J, Fayet A, Arab-Alameddine M, et al.In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function[J]. Pharmacogenet Genomics, 2009, 19(4): 300-309.
[18]	Mwenifumbo JC, Tyndale RF.Genetic variability in CYP2A6 and the pharmacokinetics of nicotine[J]. Pharmacogenomics, 2007, 8(10): 1385-1402.
[19]	Hofmann MH, Blievernicht JK, Klein K, et al.Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver[J]. J Pharmacol Exp Ther, 2008, 325(1): 284-292.
[20]	Hwang IC, Park JY, Ahn HY, et al.Effects of CYP3A5, CYP2C19, and CYP2B6 on the clinical efficacy and adverse outcomes of sibutramine therapy: A crucial role for the CYP2B6*6 allele[J]. Clin Chim Acta, 2014, 428(3): 77-81.
[21]	Johnstone E, Benowitz N, Cargill A, et al.Determinants of the rate of nicotine metabolism and effects on smoking behavior[J]. Clin Pharmacol Ther, 2006, 80(4): 319-330.
[22]	Klein K, Lang T, Saussele T, et al.Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz[J]. Pharmacogenet Genomics, 2005, 15(12): 861-873.
[23]	Klein TE, Altman RB, Eriksson N, et al.International warfarin pharmacogenetics consortium, estimation of the warfarin dose with clinical and pharmacogenetic data[J]. N Engl J Med, 2009, 360(4): 753-764.
[24]	Huang SW, Chen HS, Wang XQ, et al.Validation of VKORC1 and CYP2C9 genotypes on inter individual warfarin maintenance dose: a prospective study in Chinese patients[J]. Pharmacogenet Genomics, 2009, 19(3): 226-234.
[25]	Brauch H, Schroth W, Eichelbaum M, et al.Clinical relevance of CYP2D6 genetics for tamoxifen response in breast cancer[J]. Breast Care,2008,3(1): 43-50.
[26]	Molanaei H, Carrero JJ, Heimbürger O, et al.Influence of the CYP2D6 polymorphism and hemodialysis on codeine disposition in patients with end-stage renal disease[J]. Eur J Clin Pharmacol, 2010, 66(3): 269-273.
[27]	Kirchheiner J, Schmidt H, Tzvetkov M, et al.Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication[J]. Pharmacogenomics J, 2007, 7(4): 257-265.
[28]	Ferreirós N, Dresen S, Hermanns-Clausen M, et al.Fatal and severe codeine intoxication in 3-year-old twins-interpretation of drug and metabolite concentrations[J]. Int J Legal Med, 2009, 123(5): 387-394.
[29]	Twardowschy CA, Werneck LC, Scola RH, et al.The role of CYP2C9 polymorphisms in phenytoin-related cerebellar atrophy[J]. Seizure, 2013, 22(3): 194-197.
[30]	Lee HW, Lim M, Lee J, et al.Frequency of CYP2C9 variant alleles, including CYP2C9*13 in a Korean population and effect on glimepiride pharmacokinetics[J]. J Clin Pharm Ther, 2012, 37(1): 105-111.
[31]	Food and Drug Administration. Guidance for industry: pharmacogenomic data submissions [A]. Department of Health and Human Services, FDA, 2005.
[32]	US Food and Drug Administration. Guidance for industry: E15 definitions for genomic biomarkers, pharmacogenomics, pharmacogenetics, genomic data and sample coding categories [A]. Rockville: FDA, 2008.
[33]	Committee for Medicinal Products for Human Use. Guideline on the use of pharmacogenetic methodologies in the pharmacokinetic evaluation of medicinal products Draft [A]. European Medicines Agency, 2010.
[34]	US Food and Drug Administration. Guidance for industry drug interaction studies-study design, data analysis, implications for dosing, and labeling recommendations [A]. Food and Drug Administration: Rockville, MD, 2012.
[35]	US Department of Health and Human Services, FDA C, CBER C. Guidance for industry: clinical pharmacogenomics: premarket evaluation in early-phase clinical studies and recommendations for labeling [A]. 2013.
[36]	Huang SM, Temple R. Is this the drug or dose for you: impact and consideration of ethnic factors in global drug development, regulatory review,clinical practice [J]. Clin Pharmacol Ther, 2008, 84(3): 287-295.本文编辑:储冀汝