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Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro
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 th...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Dove Medical Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907640/ https://www.ncbi.nlm.nih.gov/pubmed/27354764 http://dx.doi.org/10.2147/DDDT.S106175 |
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author | Wang, Zhe Wang, Li Xu, Ren-ai Zhan, Yun-yun Huang, Cheng-ke Dai, Da-peng Cai, Jian-ping Hu, Guo-xin |
author_facet | Wang, Zhe Wang, Li Xu, Ren-ai Zhan, Yun-yun Huang, Cheng-ke Dai, Da-peng Cai, Jian-ping Hu, Guo-xin |
author_sort | Wang, Zhe |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4907640 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-49076402016-06-28 Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro Wang, Zhe Wang, Li Xu, Ren-ai Zhan, Yun-yun Huang, Cheng-ke Dai, Da-peng Cai, Jian-ping Hu, Guo-xin Drug Des Devel Ther Original Research 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. Dove Medical Press 2016-06-08 /pmc/articles/PMC4907640/ /pubmed/27354764 http://dx.doi.org/10.2147/DDDT.S106175 Text en © 2016 Wang et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Wang, Zhe Wang, Li Xu, Ren-ai Zhan, Yun-yun Huang, Cheng-ke Dai, Da-peng Cai, Jian-ping Hu, Guo-xin Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro |
title | Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro |
title_full | Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro |
title_fullStr | Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro |
title_full_unstemmed | Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro |
title_short | Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro |
title_sort | role of cytochrome p450 2d6 genetic polymorphism in carvedilol hydroxylation in vitro |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907640/ https://www.ncbi.nlm.nih.gov/pubmed/27354764 http://dx.doi.org/10.2147/DDDT.S106175 |
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