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In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population
Author(s) -
Dai DaPeng,
Geng PeiWu,
Wang ShuangHu,
Cai Jie,
Hu LiMing,
Nie JingJing,
Hu JiHong,
Hu GuoXin,
Cai JianPing
Publication year - 2015
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12363
Subject(s) - cyp2d6 , dextromethorphan , biology , gene isoform , genetics , allele , population , phenotype , isozyme , enzyme , gene , pharmacology , genotype , biochemistry , medicine , environmental health
Cytochrome P450 2D6 ( CYP 2D6) is one of the most widely investigated CYP s related to genetic polymorphisms and is responsible for one‐quarter of the currently used clinical drugs. We previously detected 22 novel, non‐synonymous, mutated sites in the Chinese population, but nothing is known about the functional effects of these mutations in terms of specific CYP 2D6 substrates. In this study, wild‐type CYP 2D6, two common allelic variants and 22 newly reported CYP 2D6 isoforms were transiently expressed in 293 FT cells, and the enzymatic activities of these variants were systematically assessed using dextromethorphan and bufuralol as the probing substrates. Consequently, 19 and 21 allelic variants were found to exhibit significantly decreased enzymatic activities for dextromethorphan and bufuralol, respectively. Of 22 novel CYP 2D6 variants, six allelic isoforms ( CYP 2D6.89, CYP 2D6.92, CYP 2D6.93, CYP 2D6.96, E215K and R440C) exhibited absent or extremely reduced metabolic activities compared with those observed for the wild‐type enzyme. Our in vitro functional data can be useful for CYP 2D6 phenotype prediction and provide valuable information for the study of clinical impact of these newly found CYP 2D6 variants in China.