Functional Interaction between Cytochrome P450 and UDP-Glucuronosyltransferase on the Endoplasmic Reticulum Membrane: One of Post-translational Factors Which Possibly Contributes to Their Inter-Individual Differences.

Cytochrome P450 (P450) and uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) catalyze oxidation and glucuronidation in drug metabolism, respectively. It is believed that P450 and UGT work separately because they perform distinct reactions and exhibit opposite membrane topologies on the endoplasmic reticulum (ER). However, given that some chemicals are sequentially metabolized by P450 and UGT, it is reasonable to consider that the enzymes may interact and work cooperatively. Previous research by our team detected protein-protein interactions between P450 and UGT by analyzing solubilized rat liver microsomes with P450-immobilized affinity column chromatography. Although P450 and UGT have been known to form homo- and hetero-oligomers, this is the first report indicating a P450-UGT association. Based on our previous study, we focused on the P450-UGT interaction and reported lines of evidence that the P450-UGT association is a functional protein-protein interaction that can alter the enzymatic capabilities, including enhancement or suppression of the activities of P450 and UGT, helping UGT to acquire novel regioselectivity, and inhibiting substrate binding to P450. Biochemical and molecular bioscientific approaches suggested that P450 and UGT interact with each other at their internal hydrophobic domains in the ER membrane. Furthermore, several in vivo studies have reported the presence of a functional P450-UGT association under physiological conditions. The P450-UGT interaction is expected to function as a novel post-translational factor for inter-individual differences in the drug-metabolizing enzymes.