Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population
Cytochrome 2C9 (CYP2C9), one of the most important drug metabolic enzymes in the human hepatic P450 superfamily, is required for the metabolism of 15% of clinical drugs. Similar to other CYP2C family members, CYP2C9 gene has a high genetic polymorphism which can cause significant racial and inter-in...
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1007268/full |
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| author | Fang-Ling Zhao Fang-Ling Zhao Qing Zhang Shuang-Hu Wang Yun Hong Shan Zhou Quan Zhou Pei-Wu Geng Qing-Feng Luo Jie-Fu Yang Hao Chen Jian-Ping Cai Da-Peng Dai Da-Peng Dai |
| author_facet | Fang-Ling Zhao Fang-Ling Zhao Qing Zhang Shuang-Hu Wang Yun Hong Shan Zhou Quan Zhou Pei-Wu Geng Qing-Feng Luo Jie-Fu Yang Hao Chen Jian-Ping Cai Da-Peng Dai Da-Peng Dai |
| author_sort | Fang-Ling Zhao |
| collection | DOAJ |
| description | Cytochrome 2C9 (CYP2C9), one of the most important drug metabolic enzymes in the human hepatic P450 superfamily, is required for the metabolism of 15% of clinical drugs. Similar to other CYP2C family members, CYP2C9 gene has a high genetic polymorphism which can cause significant racial and inter-individual differences in drug metabolic activity. To better understand the genetic distribution pattern of CYP2C9 in the Chinese Han population, 931 individuals were recruited and used for the genotyping in this study. As a result, seven synonymous and 14 non-synonymous variations were identified, of which 4 missense variants were designated as new alleles CYP2C9*72, *73, *74 and *75, resulting in the amino acid substitutions of A149V, R150C, Q214H and N418T, respectively. When expressed in insect cell microsomes, all four variants exhibited comparable protein expression levels to that of the wild-type CYP2C9 enzyme. However, drug metabolic activity analysis revealed that these variants exhibited significantly decreased catalytic activities toward three CYP2C9 specific probe drugs, as compared with that of the wild-type enzyme. These data indicate that the amino acid substitution in newly designated variants can cause reduced function of the enzyme and its clinical significance still needs further investigation in the future. |
| first_indexed | 2024-04-11T14:03:48Z |
| format | Article |
| id | doaj.art-82e7e3b0ff074e13897a7243a48384c2 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T14:03:48Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-82e7e3b0ff074e13897a7243a48384c22022-12-22T04:19:57ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-12-011310.3389/fphar.2022.10072681007268Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han populationFang-Ling Zhao0Fang-Ling Zhao1Qing Zhang2Shuang-Hu Wang3Yun Hong4Shan Zhou5Quan Zhou6Pei-Wu Geng7Qing-Feng Luo8Jie-Fu Yang9Hao Chen10Jian-Ping Cai11Da-Peng Dai12Da-Peng Dai13The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, ChinaPeking University Fifth School of Clinical Medicine, Beijing, ChinaDepartment of Cardiovascular, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaLaboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, ChinaDepartment of Gastroenterology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaPeking University Fifth School of Clinical Medicine, Beijing, ChinaLaboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, ChinaLaboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, ChinaDepartment of Gastroenterology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Cardiovascular, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Cardiovascular, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, ChinaPeking University Fifth School of Clinical Medicine, Beijing, ChinaCytochrome 2C9 (CYP2C9), one of the most important drug metabolic enzymes in the human hepatic P450 superfamily, is required for the metabolism of 15% of clinical drugs. Similar to other CYP2C family members, CYP2C9 gene has a high genetic polymorphism which can cause significant racial and inter-individual differences in drug metabolic activity. To better understand the genetic distribution pattern of CYP2C9 in the Chinese Han population, 931 individuals were recruited and used for the genotyping in this study. As a result, seven synonymous and 14 non-synonymous variations were identified, of which 4 missense variants were designated as new alleles CYP2C9*72, *73, *74 and *75, resulting in the amino acid substitutions of A149V, R150C, Q214H and N418T, respectively. When expressed in insect cell microsomes, all four variants exhibited comparable protein expression levels to that of the wild-type CYP2C9 enzyme. However, drug metabolic activity analysis revealed that these variants exhibited significantly decreased catalytic activities toward three CYP2C9 specific probe drugs, as compared with that of the wild-type enzyme. These data indicate that the amino acid substitution in newly designated variants can cause reduced function of the enzyme and its clinical significance still needs further investigation in the future.https://www.frontiersin.org/articles/10.3389/fphar.2022.1007268/fullCYP2C9drug metabolismallelic variantbaculovirusmicrosome |
| spellingShingle | Fang-Ling Zhao Fang-Ling Zhao Qing Zhang Shuang-Hu Wang Yun Hong Shan Zhou Quan Zhou Pei-Wu Geng Qing-Feng Luo Jie-Fu Yang Hao Chen Jian-Ping Cai Da-Peng Dai Da-Peng Dai Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population Frontiers in Pharmacology CYP2C9 drug metabolism allelic variant baculovirus microsome |
| title | Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population |
| title_full | Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population |
| title_fullStr | Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population |
| title_full_unstemmed | Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population |
| title_short | Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population |
| title_sort | identification and drug metabolic characterization of four new cyp2c9 variants cyp2c9 72 75 in the chinese han population |
| topic | CYP2C9 drug metabolism allelic variant baculovirus microsome |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1007268/full |
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