Evidence for functional interaction between phase I and phase II drug metabolizing enzymes

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Functional protein-protein interaction between phase I and phase II drug metabolizing enzymes was studied. While many cytochrome P450 (P450) enzymes associate nonspecifically with microsomal epoxide hydrolase (mEH), the CYP2C11 plays a greater role in the association/activation of mEH. In addition, P450-mediated activation of mEH depends upon the substrate of mEH. Thus, protein-protein interaction between P450 and mEH modulates mEH function. On the other hand, a UGT isoform(s) involved in 3-hydroxybenzo(a)pyrene glucuronidation is interfered by a CYP1A inhibitor, alpha-naphthoflavone via a mechanism dependent on the intact nature of microsomal membranes in 3-methyl-cholanthrene-treated rats. It is likely that P450 functions as a substrate supplier for some isoforms of UGT via possible interactions between UGT and P450. Further, a major human P450, CYP3A4 interacts with and modulates UGT2B7-catalyzed morphine glucuronidation. CYP3A4 alters UGT2B7 regioselectivity so that the ratio of morphine activation/detoxication is increased. This study provides the first evidence that P450 is not only involved in oxidation of drugs but also modulates the function of UGTs. Functional interaction between drug metabolizing enzymes may finely tune to eliminate various kinds of drugs and environmental pollutants.