Current views on the fundamental mechanisms of cytochrome P450 allosterism.

Clinically relevant cytochrome P450 (CYP)-dependent drug metabolism and drug-drug interactions remain difficult to predict on the basis of in vitro data. One contribution to this difficulty is the complex allosteric kinetics that CYPs exhibit in vitro. In principle, an understanding of this behaviour at the molecular level could improve in vitro-in vivo correlations and prediction of in vivo 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.