Functional Assessment of 12 Rare Allelic CYP2C9 Variants Identified in a Population of 4773 Japanese Individuals.

摘要: Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% clinically used drugs, including warfarin, which known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by genetic polymorphisms lead inconsistent treatment responses patients. Thus, this study, we characterized functional wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified 4773 Japanese individuals. These were heterologously expressed 293FT cells, kinetic parameters (Km, kcat, Vmax, catalytic efficiency, CLint) (S)-warfarin 7-hydroxylation tolbutamide 4-hydroxylation estimated. From analysis, almost all showed significantly reduced or null compared with wild-type. A strong correlation was found efficiencies between among studied variants. The causes observed perturbation evaluated three-dimensional structural modeling. Our findings could clarify a part discrepancies genotype-phenotype associations based on allelic could, therefore, improve personalized medicine, selection appropriate warfarin dose.