title: Comparison of cytochrome P450 2C subfamily members in terms of drug oxidation rates and substrate inhibition.
abstract: This review focuses on identification of important active-site residues of the cytochrome P450 2C (CYP2C) subfamily in terms of substrate specificity. A meta-analysis was performed on the reported literature regarding (1) values of the Michaelis-Menten constant (K(m)), maximal velocity (V(max)), and intrinsic clearance (V(max)/K(m)) for 74 metabolic reactions of 45 substrates mediated by human CYP2C8, CYP2C9, CYP2C18, and CYP2C19 and (2) inhibition constants (K(i)) for 3 inhibitors. Although the kinetic behaviors of these CYP2C subfamily members depend on the metabolic reaction, the ratios of V(max)/K(m) values for CYP2C19/CYP2C9 and CYP2C8/CYP2C19, but not for CYP2C8/CYP2C9, were more closely correlated with K(m) values than with V(max) values, suggesting that, for many metabolic reactions, differences in affinity may be more important than differences in capacity for the substrate/reaction specificity of the CYP2C subfamily, especially for CYP2C19. In addition, it has been proposed that the residues involved in substrate recognition sites (SRS) 1, SRS 3, and/or SRS 4 are important for the metabolizing capacity and/or the substrate binding of CYP2C9 and CYP2C19. In contrast to the reasonable amount of kinetic data available, there are few reports comparing the effects of inhibitors [inhibitory constant (K(i)) or 50% inhibitory concentration (IC(50))] on metabolic reactions mediated by the CYP2C subfamily. Collectively, these findings provide insights into the contributions of CYP2C subfamily members to drug metabolism and adverse drug interactions.
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niwa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System