Current views on the fundamental mechanisms of cytochrome P450 allosterism

Abstract

Clinically relevant cytochrome P450 (CYP)-dependent drug metabolism and drugdrug interactions remain difficult to predict on the basis of invitro data. One contribution to this difficulty is the complex allosteric kinetics that CYPs exhibit invitro. In principle, an understanding of this behaviour at the molecular level could improve invitroinvivo correlations and prediction of invivo drug behaviour. Recent results suggest a multiplicity of allosteric mechanisms, including drug-dependent conformational changes and protein conformational heterogeneity, occupancy by separate drug molecules of discrete binding sites, potentially at remote locations, and drug concentration-dependent or effector concentration-dependent orientation within the active site of the drug being metabolised. Most importantly, the recent research provides optimism that we can understand these complex enzymes; the research has included the creative use of biophysical techniques previously thought to be inapplicable to CYPs.

Keywords::

• allosteric drug interactions
• atypical kinetics
• drug interactions
• in vitro drug metabolism