Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C972-75 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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| Published in | Frontiers in Pharmacology Vol. 13; p. 1007268 |
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| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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13.12.2022
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| Abstract | 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. |
|---|---|
| AbstractList | 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,
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
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
,
,
and
, 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. 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.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. 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. 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. |
| Author | Pei-Wu Geng Yun Hong Da-Peng Dai Hao Chen Shuang-Hu Wang Qing-Feng Luo Jian-Ping Cai Fang-Ling Zhao Shan Zhou Qing Zhang Quan Zhou Jie-Fu Yang |
| AuthorAffiliation | 4 Laboratory of Clinical Pharmacy , The Sixth Affiliated Hospital of Wenzhou Medical University , The People’s Hospital of Lishui , Lishui , China 2 Peking University Fifth School of Clinical Medicine , Beijing , China 1 The 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 , China 3 Department of Cardiovascular , Beijing Hospital , National Center of Gerontology , Institute of Geriatric Medicine , Chinese Academy of Medical Sciences , Beijing , China 5 Department of Gastroenterology , Beijing Hospital , National Center of Gerontology , Institute of Geriatric Medicine , Chinese Academy of Medical Sciences , Beijing , China |
| AuthorAffiliation_xml | – name: 2 Peking University Fifth School of Clinical Medicine , Beijing , China – name: 4 Laboratory of Clinical Pharmacy , The Sixth Affiliated Hospital of Wenzhou Medical University , The People’s Hospital of Lishui , Lishui , China – name: 5 Department of Gastroenterology , Beijing Hospital , National Center of Gerontology , Institute of Geriatric Medicine , Chinese Academy of Medical Sciences , Beijing , China – name: 1 The 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 , China – name: 3 Department of Cardiovascular , Beijing Hospital , National Center of Gerontology , Institute of Geriatric Medicine , Chinese Academy of Medical Sciences , Beijing , China |
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| Cites_doi | 10.1016/S0140-6736(02)11203-7 10.1038/nature01862 10.1002/cpt.2321 10.1254/jphs.13189FP 10.2147/Pgpm.S272015 10.1002/cpt.1651 10.1016/j.pharmthera.2012.12.007 10.1002/prp2.718 10.3109/00498254.2013.820007 10.1093/nar/gkg509 10.1046/j.1365-2125.1998.00721.x 10.1146/annurev-genom-083118-014845 10.1097/00008571-199402000-00005 10.1038/s41586-020-2308-7 10.1097/01.fpc.0000114759.08559.51 10.1042/BJ20021841 10.1111/cts.12758 10.1080/00498254.2019.1648911 10.1208/aapsj080112 10.1016/j.ajhg.2021.07.001 10.1038/aps.2013.123 10.1016/j.cld.2016.08.001 10.2217/pgs.15.89 10.1097/01.fpc.0000215069.14095.c6 10.1124/dmd.115.063412 10.1097/FPC.0000000000000172 10.1124/dmd.109.027003 10.1016/j.mayocp.2013.10.021 10.2174/1389450118666170125144557 10.1124/jpet.105.091181 10.1038/524503a 10.1097/FPC.0b013e3283544062 10.1016/j.cbi.2020.109168 10.1016/j.bbagen.2006.07.005 10.1038/tpj.2013.2 10.1016/j.phrs.2022.106087 10.1002/cpt.2333 10.1038/nmeth0410-248 10.1074/jbc.M405427200 10.1021/acs.biochem.7b00795 10.1016/j.clpt.2004.04.001 10.1080/17425255.2021.1921147 10.1080/03602530902843483 10.3390/ijms222312808 10.1016/bs.apha.2018.04.007 |
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| Keywords | CYP2C9 allelic variant baculovirus microsome drug metabolism |
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| Title | Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C972-75 in the Chinese Han population |
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