6533b857fe1ef96bd12b4dab

RESEARCH PRODUCT

DRUG-DRUG INTERACTIONS VIA INHIBITION OF MICROSOMAL ENZYMES INVOLVED IN METABOLISM OF EPOXIDES PRODUCED BY MICROSOMAL MONOOXYGENASE

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SUMMARY Benzo(a)pyrene was activated by liver microsomes to mutagens detected by the reversion of histidine dependent Salmonella typhimurium TA 1537. Using pure epoxide hydratase or epoxide hydratase inhibitors, comparing animal species with high and low epoxide hydratase activity, or inducing monooxygenase activity, it was shown that epoxide hydratase was a critical enzyme for the inactivation of these mutagens. Many clinically used drugs are metabolized to epoxides. Epoxides are not necessarily mutagenic, but since epoxide hydratase has a very low substrate specificity, such epoxides may competitively inhibit the hydration of mutagenic epoxides, as demonstrated in the present study for the metabolically produced epoxide from the clinically used drug cyproheptadine. Interestingly the structurally closely related epoxide derived from carbamazepine did not significantly inhibit epoxide hydratase. In a therapeutic situation it would be expected that the concentration of the epoxides metabolically produced from the drug would be much greater than that of the epoxides produced from polycyclic hydrocarbons which are present ubiquitously, but at very low levels. Thus, competitive inhibition by the former may be very effective and may potentiate adverse biological effects of the latters.