Phenylbutazone-dependent epoxidation of 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene. A new mechanism for prostaglandin H synthase-catalyzed oxidations.
The nonsteroidal anti-inflammatory drug phenylbutazone markedly enhances the hydroperoxide-dependent epoxidation of 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene catalyzed by microsomal and Tween-20 solubilized preparations of prostaglandin H synthase. Furthermore, phenylbutazone radically alters the hydroperoxide specificity of 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene epoxidation. In the absence of phenylbutazone, only allylic hydroperoxides are effective in initiating epoxidation, whereas in the presence of phenylbutazone the reaction can be initiated by t-butyl hydroperoxide, cumene hydroperoxide, and hydrogen peroxide. All effects are dependent on the concentration of phenylbutazone present. The primary event is the oxidation of phenylbutazone by prostaglandin H synthase. This pathway yields a peroxy radical of phenylbutazone which appears to be the epoxidizing agent. This activation of a primary substrate by a peroxidase resulting in metabolism of a secondary substrate is analogous to the halogenation reactions catalyzed by chloroperoxidase. This represents a new class of oxidation reactions catalyzed by prostaglandin H synthase.
D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism*; D004101:Dihydroxydihydrobenzopyrenes; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D008861:Microsomes / Q000201:enzymology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010653:Phenylbutazone / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D012669:Seminal Vesicles / Q000201:enzymology; D012756:Sheep
D001580:Benzopyrenes; D004101:Dihydroxydihydrobenzopyrenes; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D011720:Pyrazoles; C017228:benzo(a)pyrene 7,8-dihydrodiol; D011451:Prostaglandin-Endoperoxide Synthases; D010653:Phenylbutazone; C015429:phenidone