NDLI: Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro

Content Provider	PubMed Central
Author	Wang, Zhe Wang, Li Xu, Ren-ai Zhan, Yun-yun Huang, Cheng-ke Dai, Da-peng Cai, Jian-ping Hu, Guo-xin
Copyright Year	2016
Abstract	Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme that catalyzes the metabolism of a great number of therapeutic drugs. Up to now, >100 allelic variants of CYP2D6 have been reported. Recently, we identified 22 novel variants in the Chinese population in these variants. The purpose of this study was to examine the enzymatic activity of the variants toward the CYP2D6 substrate carvedilol in vitro. The CYP2D6 proteins, including CYP2D6.1 (wild type), CYP2D6.2, CYP2D6.10, and 22 other novel CYP2D6 variants, were expressed from insect microsomes and incubated with carvedilol ranging from 1.0 μM to 50 μM at 37°C for 30 minutes. After termination, the carvedilol metabolites were extracted and detected using ultra-performance liquid chromatography tandem mass-spectrometry. Among the 24 CYP2D6 variants, CYP2D6.92 and CYP2D6.96 were catalytically inactive and the remaining 22 variants exhibited significantly decreased intrinsic clearance values (ranging from ~25% to 95%) compared with CYP2D6.1. The present data in vitro suggest that the newly found variants significantly reduced catalytic activities compared with CYP2D6.1. Given that CYP2D6 protein activities could affect carvedilol plasma levels, these findings are greatly relevant to personalized medicine.
Related Links	http://dx.doi.org/10.2147/dddt.s106175
Ending Page	1916
Starting Page	1909
File Format	PDF
ISSN	11778881
e-ISSN	11778881
Journal	Drug Design, Development and Therapy
Volume Number	10
Language	English
Publisher	Dove Medical Press
Publisher Date	2016-06-01
Access Restriction	Open
Rights Holder	Dove Medical Press
Subject Keyword	Pharmacology Drug Discovery Pharmaceutical Science Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Pharmacology Pharmaceutical Science

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