In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

Cytochrome P450 2D6 (CYP2D6) is one of the most widely investigated CYPs 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...

Full description

Saved in:
Bibliographic Details
Published in:Basic & clinical pharmacology & toxicology 2015-07, Vol.117 (1), p.39-43
Main Authors: Dai, Da‐Peng, Geng, Pei‐Wu, Wang, Shuang‐Hu, Cai, Jie, Hu, Li‐Ming, Nie, Jing‐Jing, Hu, Ji‐Hong, Hu, Guo‐Xin, Cai, Jian‐Ping
Format: Article
Language:English
Subjects:
Asian Continental Ancestry Group - genetics
China - epidemiology
Cytochrome P-450 CYP2D6 - genetics
Cytochrome P-450 CYP2D6 - metabolism
Dextromethorphan - metabolism
Ethanolamines - metabolism
Gene Frequency
Genotype
HEK293 Cells
Humans
Mutation
Phenotype
Substrate Specificity
Transfection
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cytochrome P450 2D6 (CYP2D6) is one of the most widely investigated CYPs 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 CYP2D6 substrates. In this study, wild‐type CYP2D6, two common allelic variants and 22 newly reported CYP2D6 isoforms were transiently expressed in 293FT 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 CYP2D6 variants, six allelic isoforms (CYP2D6.89, CYP2D6.92, CYP2D6.93, CYP2D6.96, 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 CYP2D6 phenotype prediction and provide valuable information for the study of clinical impact of these newly found CYP2D6 variants in China.
ISSN:1742-7835
1742-7843
DOI:10.1111/bcpt.12363