Effects of 24 CYP2D6 variants found in Chinese population on the metabolism of clonidine in vitro

doi:10.1016/j.cbi.2019.108840

科研成果详情

题名	Effects of 24 CYP2D6 variants found in Chinese population on the metabolism of clonidine in vitro
作者	Li, Xiang-yu 1; Hu, Xiao-xia 2; Yang, Fang 1; Yuan, Ling-jing 3; Cai, Jian-ping 4; Hu, Guo-xin5
发表日期	2019-11-01
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 Clonidine Genetic polymorphisms Allelic variants Drug metabolism
其他关键词	TOURETTE SYNDROME ; FUNCTIONAL-CHARACTERIZATION ; GENETIC-POLYMORPHISM ; CYTOCHROME-P450 2D6 ; ALLELIC VARIANTS ; TIC DISORDERS ; WILD-TYPE ; CHILDREN ; 4-HYDROXYLATION
摘要	Background and objectives: Clonidine has been clinically used to treat Tourette's syndrome for decades. There was research finding that clonidine possessed the best risk-benefit ratio, especially for patients associated with attention deficit hyperactivity disorder. CYP2D6 is a significant member of Cytochrome P450 enzymes. The genetic polymorphisms of CYP2D6 greatly affect the clinical effects of drugs even lead to side effects and medical malpractice. Our goal is to research the effect of CYP2D6 genetic polymorphism on the metabolism of clonidine and evaluate the functions of 22 CYP2D6 allelic variants in vitro, which were discovered in Chinese Han population recently. Methods: This study was carried out through a mature incubation system. The wild-type CYP2D61 and 24 variants (CYP2D62, CYP2D610 and 22 novel CYP2D6 variants) were expressed in insect cells, and the catalytic activity of all the variants were assessed by substrate clonidine. Metabolite 4-OH clonidine was accurately detected via ultra-performance liquid-chromatography tandem mass spectrometry to evaluate the effect of CYP2D6 genetic polymorphism on the clonidine. Result: Among the 22 novel CYP2D6 variants, the intrinsic clearance (Vmax/Km) of 21 variants were significantly decreased (from 1.53% to 83.25%) compared to the wild-type. In particular, the following seven variants (CYP2D6 2, CYP2D6* 10, CYP2D6* 93, CYP2D6* 95, E215K, V327 M and R497C) attract more attention, of which the intrinsic clearance decreased more than 70% compared to the wild-type. Because the variants with significantly reduced intrinsic clearance are more likely to cause adverse reactions than the variants with increased or little changed intrinsic clearance. In addition, the related pharmacokinetic parameters of CYP2D692 and CYP2D696 could not be acquired for the defect of CYP2D6 nucleotide. Conclusion: We comprehensively evaluated the effect of 22 novel CYP2D6 variants on the metabolism of clonidine for the first time and hoped corresponding data provide a reference for metabolism of clonidine for further studies in vivo, and extend our understanding of the clinical drug toxicity or ineffectiveness by CYP2D6 genetic polymorphism.
资助项目	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [NSFC 81973397]
出版者	ELSEVIER IRELAND LTD
出版地	CLARE
ISSN	0009-2797
EISSN	1872-7786
卷号	313 页码:108840
DOI	10.1016/j.cbi.2019.108840
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:000490548100002
收录类别	SSCI ; SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	31585114
SCOPUSEID	2-s2.0-85072852476
通讯作者地址	[Hu, Guo-xin]Department of Pharmacology,School of Pharmacy of Wenzhou Medical University,Wenzhou,China
Scopus学科分类	Toxicology
引用统计	被引频次：6[WOS] [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/2759
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 Pharmacy,Shaoxing Keqiao Women & Children΄s Hospital,Shaoxing,China; 2.Department of Pharmacy,Jinhua Municipal Central Hospital,Jinhua,China; 3.Department of Pharmacy,Shaoxing Second Hospital,Shaoxing,China; 4.The Key Laboratory of Geriatrics,Beijing Hospital & Beijing Institute of Geriatrics,Ministry of Health,Beijing,100730,China; 5.Department of Pharmacology,School of Pharmacy of Wenzhou Medical University,Wenzhou,China
通讯作者单位	临床药学与药理系
推荐引用方式 GB/T 7714	Li, Xiang-yu,Hu, Xiao-xia,Yang, Fang,et al. Effects of 24 CYP2D6 variants found in Chinese population on the metabolism of clonidine in vitro[J]. CHEMICO-BIOLOGICAL INTERACTIONS,2019,313:108840.
APA	Li, Xiang-yu, Hu, Xiao-xia, Yang, Fang, Yuan, Ling-jing, Cai, Jian-ping, & Hu, Guo-xin. (2019). Effects of 24 CYP2D6 variants found in Chinese population on the metabolism of clonidine in vitro. CHEMICO-BIOLOGICAL INTERACTIONS, 313, 108840.
MLA	Li, Xiang-yu,et al."Effects of 24 CYP2D6 variants found in Chinese population on the metabolism of clonidine in vitro".CHEMICO-BIOLOGICAL INTERACTIONS 313(2019):108840.