Effect of 22 CYP2D6 variants found in the Chinese population on tolterodine metabolism in vitro

doi:10.1016/j.cbi.2017.01.003

科研成果详情

题名	Effect of 22 CYP2D6 variants found in the Chinese population on tolterodine metabolism in vitro
作者	Wang, Hao 1; Dai, Da-Peng 2; Sun, Peng 1; Xu, Li-Ping1; Liang, Bing-Qing 1; Cai, Jian-Ping 2; Hu, Guo-Xin1
发表日期	2017-02-25
发表期刊	CHEMICO-BIOLOGICAL INTERACTIONS 影响因子和分区
语种	英语
原始文献类型	Article
关键词	CYP2D6 Allelic variants Tolterodine Drug metabolism In vitro
其他关键词	HUMAN CYTOCHROME-P450 2D6 ; FUNCTIONAL-CHARACTERIZATION ; GENETIC POLYMORPHISMS ; CLINICAL-SIGNIFICANCE ; MOLECULAR-GENETICS ; CATALYTIC ACTIVITY ; ALLELIC ISOFORMS ; DRUG DEVELOPMENT ; HAN POPULATION ; PHARMACOGENOMICS
摘要	Cytochrome P450 2D6 (CYP2D6) is an important member of the cytochrome P450 enzyme superfamily. We recently identified 22 novel variants in the Chinese population using PCR and bidirectional sequencing methods. The aim of this study is to characterize the enzymatic activity of these variants and their effects on the metabolism of the antimuscarinic drug tolterodine in vitro. A baculovirus-mediated expression system was used to express wild-type CYP2D6 and 24 variants (CYP2D62, CYP2D610, and 22 novel CYP2D6 variants) at high levels. The insect microsomes expressing CYP2D6 proteins were incubated with 0.1-50 mu M tolterodine at 37 degrees C for 30 min and the metabolites were analyzed by high-performance liquid chromatography tandem mass spectrometry system. Of the 24 CYP2D6 variants tested, 2 variants (CYP2D692 and CYP2D696) were found to be catalytically inactive, 4 variants (CYP2D694, F164L, F219S and D336N) exhibited markedly increased intrinsic clearance values (V-max/K-m) compared with the wild-type (from 6634 to 99.79%), whereas 4 variants (CYP2D610, 93, 95 and E215K) exhibited significantly decreased values (from 49.02 to 98.50%). This is the first report of all these rare alleles for tolterodine metabolism and these findings suggest that more attention should be paid to subjects carrying these infrequent CYP2D6 alleles when administering tolterodine in the clinic. (C) 2017 Published by Elsevier Ireland Ltd.
资助项目	National Department Public Benefit Research Foundation by the Ministry of Health of the People's Republic of China [201302008]; grant from the National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31371280]
出版者	ELSEVIER IRELAND LTD
出版地	CLARE
ISSN	0009-2797
EISSN	1872-7786
卷号	264 页码:10-15
DOI	10.1016/j.cbi.2017.01.003
页数	6
WOS类目	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Toxicology
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Toxicology
WOS记录号	WOS:000395229500002
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	28087463
SCOPUSEID	2-s2.0-85010022047
通讯作者地址	[Hu, Guo-Xin]Department of Pharmacology,School of Pharmacy of Wenzhou Medical University,Wenzhou,325035,China
Scopus学科分类	Toxicology
引用统计	被引频次[WOS]：0 [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/4509
专题	药学院（分析测试中心）药学院（分析测试中心）_临床药学与药理系
通讯作者	Hu, Guo-Xin
作者单位	1.Department of Pharmacology,School of Pharmacy of Wenzhou Medical University,Wenzhou,325035,China; 2.The Key Laboratory of Geriatrics,Beijing Hospital & Beijing Institute of Geriatrics,Ministry of Health,Beijing,100730,China
第一作者单位	临床药学与药理系
通讯作者单位	临床药学与药理系
第一作者的第一单位	临床药学与药理系
推荐引用方式 GB/T 7714	Wang, Hao,Dai, Da-Peng,Sun, Peng,et al. Effect of 22 CYP2D6 variants found in the Chinese population on tolterodine metabolism in vitro[J]. CHEMICO-BIOLOGICAL INTERACTIONS,2017,264:10-15.
APA	Wang, Hao., Dai, Da-Peng., Sun, Peng., Xu, Li-Ping., Liang, Bing-Qing., ... & Hu, Guo-Xin. (2017). Effect of 22 CYP2D6 variants found in the Chinese population on tolterodine metabolism in vitro. CHEMICO-BIOLOGICAL INTERACTIONS, 264, 10-15.
MLA	Wang, Hao,et al."Effect of 22 CYP2D6 variants found in the Chinese population on tolterodine metabolism in vitro".CHEMICO-BIOLOGICAL INTERACTIONS 264(2017):10-15.