2. Academic Validation
  3. Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C9*59

Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C9*59

  • Drug Metab Dispos. 2015 Aug;43(8):1246-9. doi: 10.1124/dmd.115.063412.
Da-Peng Dai 1,  Shuang-Hu Wang 1,  Chuan-Bao Li 1,  Pei-Wu Geng 1,  Jie Cai 1,  Hao Wang 1,  Guo-Xin Hu 2,  Jian-Ping Cai 2
Affiliations

Affiliations

  • 1 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.).
  • 2 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.
PMID: 25994031 DOI: 10.1124/dmd.115.063412
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.

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