PT - JOURNAL ARTICLE AU - Da-Peng Dai AU - Shuang-Hu Wang AU - Chuan-Bao Li AU - Pei-Wu Geng AU - Jie Cai AU - Hao Wang AU - Guo-Xin Hu AU - Jian-Ping Cai TI - Identification and Functional Assessment of a New <em>CYP2C9</em> Allelic Variant <em>CYP2C9*59</em> AID - 10.1124/dmd.115.063412 DP - 2015 Aug 01 TA - Drug Metabolism and Disposition PG - 1246--1249 VI - 43 IP - 8 4099 - http://dmd.aspetjournals.org/content/43/8/1246.short 4100 - http://dmd.aspetjournals.org/content/43/8/1246.full SO - Drug Metab Dispos2015 Aug 01; 43 AB - 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&gt;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&gt;T mutation can greatly decrease the enzymatic activity of the CYP2C9 protein both in vitro and in vivo.