title: Effects of 22 Novel CYP2D6 Variants Found in the Chinese Population on the Bufuralol and Dextromethorphan Metabolisms In Vitro.
abstract: Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme that metabolizes a large number of therapeutic drugs. To date, more than 100 CYP2D6 allelic variants have been reported. Among these variants, we recently identified 22 novel variants in the Chinese population. The aim of this study was to functionally characterize the enzymatic activity of these variants in vitro. A baculovirus-mediated expression system was used to express wild-type CYP2D6.1 and other variants (CYP2D6.2, CYP2D6.10 and 22 novel CYP2D6 variants) at high levels. Then, the insect microsomes containing expressed CYP2D6 proteins were incubated with bufuralol or dextromethorphan at 37°C for 20 or 25 min., respectively. After termination, the metabolites were extracted and used for the detection with high-performance liquid chromatography. Among the 24 CYP2D6 variants tested, two variants (CYP2D6.92 and CYP2D6.96) were found to be catalytically inactive. The remaining 22 variants exhibited significantly decreased intrinsic clearance values for bufuralol 1'-hydroxylation and 20 variants showed significantly lower intrinsic clearance values for dextromethorphan O-demethylation than those of the wild-type CYP2D6.1. Our in vitro results suggest that most of the variants exhibit significantly reduced catalytic activities compared with the wild-type, and these data provide valuable information for personalized medicine in Chinese and other Asian populations.
authors: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China.|Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, China.|Department of Pharmacy, Traditional Chinese Medical Hospital of Wenling, Wenling, China.
authors: Jie
authors: J
authors: Cai
authors: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China.
authors: Da-Peng
authors: DP
authors: Dai
authors: The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, China.
authors: Pei-Wu
authors: PW
authors: Geng
authors: The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, China.
authors: Shuang-Hu
authors: SH
authors: Wang
authors: Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, China.
authors: Hao
authors: H
authors: Wang
authors: Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, China.
authors: Yun-Yun
authors: YY
authors: Zhan
authors: Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, China.
authors: Xiang-Xin
authors: XX
authors: Huang
authors: Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, China.
authors: Guo-Xin
authors: GX
authors: Hu
authors: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China.
authors: Jian-Ping
authors: JP
authors: Cai
mesh_terms: D000483:Alleles; D000818:Animals; D044466:Asian People / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003915:Dextromethorphan / Q000493:pharmacokinetics*; D004983:Ethanolamines / Q000493:pharmacokinetics*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D007313:Insecta / Q000166:cytology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D004983:Ethanolamines; D003915:Dextromethorphan; C010831:bufuralol; D019389:Cytochrome P-450 CYP2D6