Functional Characterization of 34 CYP2A6 Allelic Variants by Assessment of Nicotine C-Oxidation and Coumarin 7-Hydroxylation Activities

被引：21

作者：

Hosono, Hiroki ^{[1
]}

Kumondai, Masaki ^{[1
]}

Maekawa, Masamitsu ^{[2
]}

Yamaguchi, Hiroaki ^{[2
]}

Mano, Nariyasu ^{[2
]}

Oda, Akifumi ^{[3
]}

Hirasawa, Noriyasu ^{[1
]}

Hiratsuka, Masahiro ^{[1
]}

机构：

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

[2] Tohoku Univ Hosp, Dept Pharmaceut Sci, Sendai, Miyagi, Japan

[3] Meijo Univ, Dept Biophys Chem, Fac Pharm, Nagoya, Aichi, Japan

来源：

DRUG METABOLISM AND DISPOSITION | 2017年 / 45卷 / 03期

关键词：

HUMAN CYTOCHROME-P450 2A6; HUMAN LIVER-MICROSOMES; BLACK-AFRICAN DESCENT; IN-VIVO; GENETIC-POLYMORPHISM; JAPANESE SMOKERS; 5-FLUOROURACIL FORMATION; ENZYMATIC-ACTIVITY; LUNG-CANCER; METABOLISM;

D O I：

10.1124/dmd.116.073494

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

CYP2A6, amember of the cytochrome P450 (P450) family, is one of the enzymes responsible for the metabolism of therapeutic drugs and such tobacco components as nicotine, 4-(methylnitrosamino)-1-(3pyridyl)- 1-butanone, and N-nitrosodiethylamine. Genetic polymorphisms in CYP2A6 are associated with individual variation in smoking behavior, drug toxicities, and the risk of developing several cancers. In this study, we conducted an in vitro analysis of 34 allelic variants of CYP2A6 using nicotine and coumarin as representative CYP2A6 substrates. These variant CYP2A6 proteins were heterologously expressed in 293FT cells, and their enzymatic activitieswere assessed on the basis of nicotine C-oxidation and coumarin 7-hydroxylation activities. Among the 34 CYP2A6 variants, CYP2A6.2, CYP2A6.5, CYP2A6.6, CYP2A6.10, CYP2A6.26, CYP2A6.36, and CYP2A6.37 exhibited no enzymatic activity, whereas 14 other variants exhibited markedly reduced activity toward both nicotine and coumarin. These comprehensive in vitro findings may provide useful insight into individual differences in smoking behavior, drug efficacy, and cancer susceptibility.

引用

页码：279 / 285

页数：7

共 38 条

[1] A novel CYP2A6 allele (CYP2A6*35) resulting in an amino-acid substitution (Asn438Tyr) is associated with lower CYP2A6 activity in vivo [J].