Functional characterization of 20 allelic variants of CYP1A2

被引：14

作者：

Ito, Miyabi ^{[1
]}

Katono, Yuki ^{[1
]}

Oda, Akifumi ^{[2
]}

Hirasawa, Noriyasu ^{[1
]}

Hiratsuka, Masahiro ^{[1
]}

机构：

[1] Tohoku Univ, Grad Sch Pharmaceut Sci, Lab Pharmacotherapy Life Style Related Dis, Sendai, Miyagi 980, Japan

[2] Kanazawa Univ, Inst Med Pharmaceut & Hlth Sci, Kanazawa, Ishikawa, Japan

来源：

DRUG METABOLISM AND PHARMACOKINETICS | 2015年 / 30卷 / 03期

关键词：

Cytochrome P450; CYP1A2; Genetic polymorphism; Phenacetin; 7-Ethoxyresorufin; THEOPHYLLINE METABOLISM; CYTOCHROME-P450; 1A2; GENE POLYMORPHISMS; ENZYMATIC-ACTIVITY; LIVER-MICROSOMES; AMINO-ACID; CAFFEINE; POPULATION; SEQUENCES; ENZYMES;

D O I：

10.1016/j.dmpk.2015.03.001

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Genetic variations in cytochrome P450 1A2 (CYP1A2) are associated with interindividual variability in the metabolism and efficacy of many medications. Twenty CYP1A2 variants harboring amino acid substitutions were analyzed for functional changes in enzymatic activity. Recombinant CYP1A2 variant proteins were heterologously expressed in COS-7 cells. Enzyme kinetic analyses were performed with two representative CYP1A2 substrates, phenacetin and 7-ethoxyresorufin. Among the 20 CYP1A2 allelic variants, CYP1A2*4, CYP1A2*6, CYP1A2*8, CYP1A2*15, CYP1A2*16, and CYP1A2*21 were inactive toward both substrates. CYP1A2*11 showed markedly reduced activity, but the changes in Km were different between the substrates. CYP1A2*14 and CYP1A2*20 exhibited increased activity compared to the wildtype enzyme, CYP1A2*1. This comprehensive in vitro assessment provided insight into the specific metabolic activities of CYP1A2 proteins encoded by variant alleles, which may to be valuable when interpreting the results of in vivo studies. Copyright (C) 2015, The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

引用

页码：247 / 252

页数：6

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