Hydroperoxide-dependent activation of p-phenetidine catalyzed by prostaglandin synthase and other peroxidases.
p-Phenetidine is metabolized by ram seminal vesicle (RSV) microsomes, horseradish peroxidase (HRP) and rat liver microsomes to protein-binding products. These reactions are very rapid and depend on the presence of arachidonic acid (AA) or various hydroperoxidases. The RSV- and HRP-mediated binding was inhibited more than 80% by the addition of reduced glutathione (1 mM) or the antioxidant butylated hydroxyanisole (0.5 mM). Indomethacin (100 microM) and acetylsalicylic acid (1 mM) reduced the AA-dependent reaction in RSV microsomes to less than 5% of control values. When hydrogen peroxide replaced AA, the RSV/H2O2-supported binding in the presence of 50 microM p-phenetidine proceeded at rates similar to that observed with RSV/AA. Unlike the AA-dependent reaction, the H2O2-supported reaction showed no inhibition of protein binding at higher p-phenetidine concns. The data in this report are consistent with a peroxidatic activation of p-phenetidine possibly involving an amine radical catalyzed by prostaglandin synthase (PGS) present in RSV microsomes as well as by other peroxidases. The mechanism for this activation and physiological implications are discussed.
D000627:Aminophenols / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002384:Catalysis; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010544:Peroxidases / Q000502:physiology*; D010628:Phenetidine / Q000378:metabolism* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011485:Protein Binding; D051381:Rats; D012669:Seminal Vesicles / Q000201:enzymology; D012756:Sheep
D000627:Aminophenols; D010628:Phenetidine; D006861:Hydrogen Peroxide; D010544:Peroxidases; D011451:Prostaglandin-Endoperoxide Synthases