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Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects

Cytochrome P450 2C9 (CYP2C9) participates in about 15% of clinical drug metabolism, and its polymorphism is associated with individual drug metabolism differences, which may lead to the adverse drug reactions (ADRs). In this study, 1163 Chinese Han individuals were recruited to investigate their dis...

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Autores principales: Zhang, Qing, Qi, Yuying, Wang, Shuanghu, Zhao, Fangling, Zou, Lili, Zhou, Quan, Geng, Peiwu, Hong, Yun, Yang, Hang, Luo, Qingfeng, Cai, Jianping, Wu, Hualan, Wang, Dongxu, Chen, Hao, Yang, Jiefu, Dai, Dapeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10052410/
https://www.ncbi.nlm.nih.gov/pubmed/37008923
http://dx.doi.org/10.3389/fendo.2023.1139805
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author Zhang, Qing
Qi, Yuying
Wang, Shuanghu
Zhao, Fangling
Zou, Lili
Zhou, Quan
Geng, Peiwu
Hong, Yun
Yang, Hang
Luo, Qingfeng
Cai, Jianping
Wu, Hualan
Wang, Dongxu
Chen, Hao
Yang, Jiefu
Dai, Dapeng
author_facet Zhang, Qing
Qi, Yuying
Wang, Shuanghu
Zhao, Fangling
Zou, Lili
Zhou, Quan
Geng, Peiwu
Hong, Yun
Yang, Hang
Luo, Qingfeng
Cai, Jianping
Wu, Hualan
Wang, Dongxu
Chen, Hao
Yang, Jiefu
Dai, Dapeng
author_sort Zhang, Qing
collection PubMed
description Cytochrome P450 2C9 (CYP2C9) participates in about 15% of clinical drug metabolism, and its polymorphism is associated with individual drug metabolism differences, which may lead to the adverse drug reactions (ADRs). In this study, 1163 Chinese Han individuals were recruited to investigate their distribution pattern of CYP2C9 gene and find out the variants that may affect their drug metabolic activities. We successfully developed a multiplex PCR amplicon sequencing method and used it for the genetic screening of CYP2C9 in a large scale. Besides the wild type CYP2C9*1, totally 26 allelic variants of CYP2C9 were detected, which included 16 previously reported alleles and 10 new non-synonymous variants that had not been listed on the PharmVar website. The characteristics of these newly detected CYP2C9 variants were then evaluated after co-expressing them with CYPOR in S. cerevisiae microsomes. Immunoblot analysis revealed that except for Pro163Ser, Glu326Lys, Gly431Arg and Ile488Phe, most of newly detected variants showed comparable protein expression levels to wild type in yeast cells. Two typical CYP2C9 probe drugs, losartan and glimepiride, were then used for the evaluation of metabolic activities of variants. As a result, 3 variants Thr301Met, Glu326Lys, and Gly431Arg almost lost their catalytic activities and most of other variants exhibited significantly elevated activities for drug metabolism. Our data not only enriches the knowledge of naturally occurring CYP2C9 variants in the Chinese Han population, but also provides the fundamental evidence for its potential clinical usage for personalized medicine in the clinic.
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spelling pubmed-100524102023-03-30 Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects Zhang, Qing Qi, Yuying Wang, Shuanghu Zhao, Fangling Zou, Lili Zhou, Quan Geng, Peiwu Hong, Yun Yang, Hang Luo, Qingfeng Cai, Jianping Wu, Hualan Wang, Dongxu Chen, Hao Yang, Jiefu Dai, Dapeng Front Endocrinol (Lausanne) Endocrinology Cytochrome P450 2C9 (CYP2C9) participates in about 15% of clinical drug metabolism, and its polymorphism is associated with individual drug metabolism differences, which may lead to the adverse drug reactions (ADRs). In this study, 1163 Chinese Han individuals were recruited to investigate their distribution pattern of CYP2C9 gene and find out the variants that may affect their drug metabolic activities. We successfully developed a multiplex PCR amplicon sequencing method and used it for the genetic screening of CYP2C9 in a large scale. Besides the wild type CYP2C9*1, totally 26 allelic variants of CYP2C9 were detected, which included 16 previously reported alleles and 10 new non-synonymous variants that had not been listed on the PharmVar website. The characteristics of these newly detected CYP2C9 variants were then evaluated after co-expressing them with CYPOR in S. cerevisiae microsomes. Immunoblot analysis revealed that except for Pro163Ser, Glu326Lys, Gly431Arg and Ile488Phe, most of newly detected variants showed comparable protein expression levels to wild type in yeast cells. Two typical CYP2C9 probe drugs, losartan and glimepiride, were then used for the evaluation of metabolic activities of variants. As a result, 3 variants Thr301Met, Glu326Lys, and Gly431Arg almost lost their catalytic activities and most of other variants exhibited significantly elevated activities for drug metabolism. Our data not only enriches the knowledge of naturally occurring CYP2C9 variants in the Chinese Han population, but also provides the fundamental evidence for its potential clinical usage for personalized medicine in the clinic. Frontiers Media S.A. 2023-03-15 /pmc/articles/PMC10052410/ /pubmed/37008923 http://dx.doi.org/10.3389/fendo.2023.1139805 Text en Copyright © 2023 Zhang, Qi, Wang, Zhao, Zou, Zhou, Geng, Hong, Yang, Luo, Cai, Wu, Wang, Chen, Yang and Dai https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Zhang, Qing
Qi, Yuying
Wang, Shuanghu
Zhao, Fangling
Zou, Lili
Zhou, Quan
Geng, Peiwu
Hong, Yun
Yang, Hang
Luo, Qingfeng
Cai, Jianping
Wu, Hualan
Wang, Dongxu
Chen, Hao
Yang, Jiefu
Dai, Dapeng
Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects
title Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects
title_full Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects
title_fullStr Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects
title_full_unstemmed Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects
title_short Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects
title_sort identification and in vitro functional assessment of 10 cyp2c9 variants found in chinese han subjects
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10052410/
https://www.ncbi.nlm.nih.gov/pubmed/37008923
http://dx.doi.org/10.3389/fendo.2023.1139805
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