Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro
Genetic polymorphism of the cytochrome P450 (CYP) gene can significantly influence the metabolism of endogenous and xenobiotic compounds. However, few studies have focused on the polymorphism of CYP2J2 and its impact on drug catalytic activity, especially in the Chinese Han population. In this study...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1186824/full |
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| author | Li-Li Zou Fang-Ling Zhao Yu-Ying Qi Shuang-Hu Wang Quan Zhou Pei-Wu Geng Yun-Fang Zhou Qing Zhang Hao Chen Da-Peng Dai Jian-Ping Cai Fu-Sui Ji Fu-Sui Ji |
| author_facet | Li-Li Zou Fang-Ling Zhao Yu-Ying Qi Shuang-Hu Wang Quan Zhou Pei-Wu Geng Yun-Fang Zhou Qing Zhang Hao Chen Da-Peng Dai Jian-Ping Cai Fu-Sui Ji Fu-Sui Ji |
| author_sort | Li-Li Zou |
| collection | DOAJ |
| description | Genetic polymorphism of the cytochrome P450 (CYP) gene can significantly influence the metabolism of endogenous and xenobiotic compounds. However, few studies have focused on the polymorphism of CYP2J2 and its impact on drug catalytic activity, especially in the Chinese Han population. In this study, we sequenced the promoter and exon regions of CYP2J2 in 1,163 unrelated healthy Chinese Han individuals using the multiplex PCR amplicon sequencing method. Then, the catalytic activities of the detected CYP2J2 variants were evaluated after recombinant expression in S. cerevisiae microsomes. As a result, CYP2J2*7, CYP2J2*8, 13 variations in the promoter region and 15 CYP2J2 nonsynonymous variants were detected, of which V15A, G24R, V68A, L166F and A391T were novel missense variations. Immunoblotting results showed that 11 of 15 CYP2J2 variants exhibited lower protein expression than wild-type CYP2J2.1. In vitro functional analysis results revealed that the amino acid changes of 14 variants could significantly influence the drug metabolic activity of CYP2J2 toward ebastine or terfenadine. Specifically, 4 variants with relatively higher allele frequencies, CYP2J2.8, 173_173del, K267fs and R446W, exhibited extremely low protein expression and defective catalytic activities for both substrates. Our results indicated that a high genetic polymorphism of CYP2J2 could be detected in the Chinese Han population, and most genetic variations in CYP2J2 could influence the expression and catalytic activity of CYP2J2. Our data significantly enrich the knowledge of genetic polymorphisms in CYP2J2 and provide new theoretical information for corresponding individualized medication in Chinese and other Asian populations. |
| first_indexed | 2024-03-13T10:01:50Z |
| format | Article |
| id | doaj.art-0762e0c80a9d4f7091733ca8585dcee7 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-13T10:01:50Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-0762e0c80a9d4f7091733ca8585dcee72023-05-23T05:04:18ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-05-011410.3389/fphar.2023.11868241186824Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitroLi-Li Zou0Fang-Ling Zhao1Yu-Ying Qi2Shuang-Hu Wang3Quan Zhou4Pei-Wu Geng5Yun-Fang Zhou6Qing Zhang7Hao Chen8Da-Peng Dai9Jian-Ping Cai10Fu-Sui Ji11Fu-Sui Ji12The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, ChinaThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, ChinaThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, ChinaThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, ChinaDepartment of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaGenetic polymorphism of the cytochrome P450 (CYP) gene can significantly influence the metabolism of endogenous and xenobiotic compounds. However, few studies have focused on the polymorphism of CYP2J2 and its impact on drug catalytic activity, especially in the Chinese Han population. In this study, we sequenced the promoter and exon regions of CYP2J2 in 1,163 unrelated healthy Chinese Han individuals using the multiplex PCR amplicon sequencing method. Then, the catalytic activities of the detected CYP2J2 variants were evaluated after recombinant expression in S. cerevisiae microsomes. As a result, CYP2J2*7, CYP2J2*8, 13 variations in the promoter region and 15 CYP2J2 nonsynonymous variants were detected, of which V15A, G24R, V68A, L166F and A391T were novel missense variations. Immunoblotting results showed that 11 of 15 CYP2J2 variants exhibited lower protein expression than wild-type CYP2J2.1. In vitro functional analysis results revealed that the amino acid changes of 14 variants could significantly influence the drug metabolic activity of CYP2J2 toward ebastine or terfenadine. Specifically, 4 variants with relatively higher allele frequencies, CYP2J2.8, 173_173del, K267fs and R446W, exhibited extremely low protein expression and defective catalytic activities for both substrates. Our results indicated that a high genetic polymorphism of CYP2J2 could be detected in the Chinese Han population, and most genetic variations in CYP2J2 could influence the expression and catalytic activity of CYP2J2. Our data significantly enrich the knowledge of genetic polymorphisms in CYP2J2 and provide new theoretical information for corresponding individualized medication in Chinese and other Asian populations.https://www.frontiersin.org/articles/10.3389/fphar.2023.1186824/fullCYP2J2polymorphismallelic variantcatalytic activityChinese Han |
| spellingShingle | Li-Li Zou Fang-Ling Zhao Yu-Ying Qi Shuang-Hu Wang Quan Zhou Pei-Wu Geng Yun-Fang Zhou Qing Zhang Hao Chen Da-Peng Dai Jian-Ping Cai Fu-Sui Ji Fu-Sui Ji Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro Frontiers in Pharmacology CYP2J2 polymorphism allelic variant catalytic activity Chinese Han |
| title | Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro |
| title_full | Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro |
| title_fullStr | Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro |
| title_full_unstemmed | Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro |
| title_short | Characterization of 15 CYP2J2 variants identified in the Chinese Han population on the metabolism of ebastine and terfenadine in vitro |
| title_sort | characterization of 15 cyp2j2 variants identified in the chinese han population on the metabolism of ebastine and terfenadine in vitro |
| topic | CYP2J2 polymorphism allelic variant catalytic activity Chinese Han |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1186824/full |
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