Functional protein-protein interaction of drug metabolizing enzymes.

Cytochrome P450 (P450, CYP), a major class of enzymes involved in Phase I drug metabolism, is expressed in the cellular endoplasmic reticulum together with other enzymes, such as microsomal epoxide hydrolase (mEH) and UDP-glucuronosyltransferase (UGT). In many cases, the metabolite produced by P450 is sequentially metabolized by other enzymes to increase its water solubility. It would be reasonable to assume that the metabolite produced by P450 is directly transferred to the other enzymes participating in its subsequent metabolism via protein-protein interactions for rapid metabolism. However, these steps have been considered to take place individually. Previously, we suggested that CYP1A1 specifically associates with mEH, UGTs and NADPH-P450 reductase. This observation strongly supports the view that there is functional cooperation between P450 and mEH/UGT to facilitate multistep drug metabolism. In recent years, accumulating evidence suggests the interaction between drug metabolizing enzymes and a change in enzymatic function by this interaction. In this review, we summarize the interaction between drug metabolizing enzymes and discuss its impact on their function.