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.
Keywords: CYP2C8, CYP2C9, CYP2C18, CYP2C19, meta-analysis, metabolic activity, inhibition constant, Cytochrome P450, 2C Subfamily, Oxidation, Substrate Inhibition, Residues, Michaelis-Menten constant, polymorphisms, Alleles.
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