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Comparison of Cytochrome P450 2C Subfamily Members in Terms of Drug Oxidation Rates and Substrate Inhibition

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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 (Km), maximal velocity (Vmax), and intrinsic clearance (Vmax/Km) for 74 metabolic reactions of 45 substrates mediated by human CYP2C8, CYP2C9, CYP2C18, and CYP2C19 and (2) inhibition constants (Ki) for 3 inhibitors. Although the kinetic behaviors of these CYP2C subfamily members depend on the metabolic reaction, the ratios of Vmax/Km values for CYP2C19/CYP2C9 and CYP2C8/CYP2C19, but not for CYP2C8/CYP2C9, were more closely correlated with Km values than with Vmax 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 (Ki) or 50% inhibitory concentration (IC50)] 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.
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Keywords: 2C Subfamily; Alleles; CYP2C18; CYP2C19; CYP2C8; CYP2C9; Cytochrome P450; Michaelis-Menten constant; Oxidation; Residues; Substrate Inhibition; inhibition constant; meta-analysis; metabolic activity; polymorphisms

Document Type: Research Article

Publication date: October 1, 2012

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  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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