title: Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C9*59.
abstract: CYP2C9, one of the most important drug-metabolizing enzymes, is responsible for metabolizing approximately 15% of clinically important drugs, including warfarin, diclofenac, and losartan. Similar to other CYP members, human CYP2C9 exhibits marked genetic polymorphisms among individuals of different ethnicities. In this study, a novel missense mutation (1300A>T) was identified in a warfarin-sensitive patient after a genetic screen of three candidate genes related to high variability in response to warfarin doses. This base transversion leads to an Ile-to-Phe amino acid substitution at codon 434 within the CYP2C9 protein, and this new variant has been named a novel allele, CYP2C9*59, by the Human CYP Allele Nomenclature Committee (http://www.cypalleles.ki.se/cyp2c9.htm). The exogenous expression of CYP2C9.59 in insect cell microsomes revealed that, despite a similar protein expression level as wild-type CYP2C9, variant CYP2C9.59 exhibited significantly reduced maximal velocity, Vmax, and/or increased Michaelis constant, Km, values toward three CYP2C9-specific substrates. Our data suggest that the 1300A>T mutation can greatly decrease the enzymatic activity of the CYP2C9 protein both in vitro and in vivo.
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.-P.D., J. C., J.-P.C.); The Clinical Laboratory of Beijing Hospital, Ministry of Health, Beijing, China (C.-B.L.); Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China (J.C., H.W., G.-X.H.); and The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, Zhejiang, China (S.-H.W., P.-W.G.).
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Dai
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.-P.D., J. C., J.-P.C.); The Clinical Laboratory of Beijing Hospital, Ministry of Health, Beijing, China (C.-B.L.); Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China (J.C., H.W., G.-X.H.); and The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, Zhejiang, China (S.-H.W., P.-W.G.).
authors.forename: Shuang-Hu
authors.initials: SH
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.-P.D., J. C., J.-P.C.); The Clinical Laboratory of Beijing Hospital, Ministry of Health, Beijing, China (C.-B.L.); Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China (J.C., H.W., G.-X.H.); and The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, Zhejiang, China (S.-H.W., P.-W.G.).
authors.forename: Chuan-Bao
authors.initials: CB
authors.lastname: Li
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.-P.D., J. C., J.-P.C.); The Clinical Laboratory of Beijing Hospital, Ministry of Health, Beijing, China (C.-B.L.); Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China (J.C., H.W., G.-X.H.); and The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, Zhejiang, China (S.-H.W., P.-W.G.).
authors.forename: Pei-Wu
authors.initials: PW
authors.lastname: Geng
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.-P.D., J. C., J.-P.C.); The Clinical Laboratory of Beijing Hospital, Ministry of Health, Beijing, China (C.-B.L.); Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China (J.C., H.W., G.-X.H.); and The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, Zhejiang, China (S.-H.W., P.-W.G.).
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.-P.D., J. C., J.-P.C.); The Clinical Laboratory of Beijing Hospital, Ministry of Health, Beijing, China (C.-B.L.); Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China (J.C., H.W., G.-X.H.); and The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, Zhejiang, China (S.-H.W., P.-W.G.).
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.-P.D., J. C., J.-P.C.); The Clinical Laboratory of Beijing Hospital, Ministry of Health, Beijing, China (C.-B.L.); Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China (J.C., H.W., G.-X.H.); and The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, Zhejiang, China (S.-H.W., P.-W.G.) caijp61@vip.sina.com hgx@wzmc.edu.cn.
authors.forename: Guo-Xin
authors.initials: GX
authors.lastname: Hu
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, China (D.-P.D., J. C., J.-P.C.); The Clinical Laboratory of Beijing Hospital, Ministry of Health, Beijing, China (C.-B.L.); Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China (J.C., H.W., G.-X.H.); and The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, Zhejiang, China (S.-H.W., P.-W.G.) caijp61@vip.sina.com hgx@wzmc.edu.cn.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Cai
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics; D003062:Codon; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism*; D014644:Genetic Variation; D005822:Genetic Vectors; D005838:Genotype; D006801:Humans; D007313:Insecta; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D008958:Models, Molecular; D011110:Polymorphism, Genetic; D014859:Warfarin / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D003062:Codon; D007527:Isoenzymes; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9