期刊
DRUG METABOLISM AND PHARMACOKINETICS
卷 30, 期 3, 页码 247-252出版社
JAPANESE SOC STUDY XENOBIOTICS
DOI: 10.1016/j.dmpk.2015.03.001
关键词
Cytochrome P450; CYP1A2; Genetic polymorphism; Phenacetin; 7-Ethoxyresorufin
资金
- Ministry of Health, Labour and Welfare (MHLW) of Japan ('Initiative to facilitate development of innovative drug, medical devices, and cellular & tissue-based product')
- Smoking Research Foundation
- Japan Research Foundation for Clinical Pharmacology
- Grants-in-Aid for Scientific Research [26460034, 15H01064] Funding Source: KAKEN
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.
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