The mechanism for the inhibition of prostaglandin H synthase-catalyzed xenobiotic oxidation by methimazole. Reaction with free radical oxidation products.
Methimazole, an irreversible, mechanism-based (suicide substrate) inhibitor of thyroid peroxidase and lactoperoxidase, also inhibits the oxidation of xenobiotics by prostaglandin hydroperoxidase. The mechanism(s) by which methimazole inhibits prostaglandin H synthase-catalyzed oxidations is not conclusively known. In studies reported here, methimazole inhibited the prostaglandin H synthase-catalyzed oxidation of benzidine, phenylbutazone, and aminopyrine in a concentration-dependent manner. Methimazole poorly supported the prostaglandin H synthase-catalyzed reduction of 5-phenyl-4-pentenyl hydroperoxide to the corresponding alcohol (5-phenyl-4-pentenyl alcohol), suggesting that methimazole is not serving as a competing reducing cosubstrate for the peroxidase. Methimazole is not a mechanism-based inhibitor of prostaglandin hydroperoxidase or horseradish peroxidase since methimazole did not inhibit the peroxidase-catalyzed, benzidine-supported reduction of 5-phenyl-4-pentenyl hydroperoxide. In contrast, methimazole inhibited the reduction of 5-phenyl-4-pentenyl hydroperoxide to 5-phenyl-4-pentenyl alcohol catalyzed by lactoperoxidase, confirming that methimazole is a mechanism-based inhibitor of that enzyme and that such inhibition can be detected by our assay. Glutathione reduces the aminopyrine cation free radical, the formation of which is catalyzed by the hydroperoxidase, back to the parent compound. Methimazole produced the same effect at concentrations equimolar to those required for glutathione. These data indicate that methimazole does not inhibit xenobiotic oxidations catalyzed by prostaglandin H synthase and horseradish peroxidase through direct interaction with the enzyme, but rather inhibits accumulation of oxidation products via reduction of a free radical-derived metabolite(s).
D000818:Animals; D016861:Cyclooxygenase Inhibitors; D005609:Free Radicals; D005978:Glutathione / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008713:Methimazole / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010544:Peroxidases; D012669:Seminal Vesicles / Q000201:enzymology; D012756:Sheep
D016861:Cyclooxygenase Inhibitors; D005609:Free Radicals; D008713:Methimazole; D010544:Peroxidases; D005978:Glutathione