Stereoselectivity of human cytochrome p450 in metabolic and inhibitory activities

This review focuses on stereoselectivity of human cytochrome P450 (P450 or CYP) in the area of metabolism and inhibition. A meta-analysis was performed based on the reported values regarding (1) values of the Michaelis-Menten constant (K(m)), maximal velocity (V(max)), and intrinsic clearance (V(max)/K(m)) for 45 metabolic reactions of 19 substrates and (2) inhibition constants (K(i)) for 6 inhibitors. The median (R)/(S)-enantiomer ratios of the K(m), V(max), and V(max)/K(m) values for CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 were in the range of 0.80-1.53, whereas the median ratios of V(max), and V(max)/K(m) values for CYP2C9 were 0.43 and 0.60, respectively. In addition, the parameters for metabolic reactions (25-80%) of (R)-enantiomers of these P450s were comparable to those of (S)-enantiomers (the ratios were between 0.5 and 2), whereas 45-69% of V(max) and V(max)/K(m) values for the (R)-enantiomer in CYP2C9 were less than half of those for the (S)-enantiomer, although the kinetic behavior of the stereoselectivity depended on the metabolic reaction. There is a limited number of reports regarding stereoselective inhibition and induction in vitro. The present information gives insight into the contribution of stereoselectivity to metabolism mediated by P450s and the risk of adverse drug-drug interactions due to stereoselectivity.