Prostaglandin hydroperoxidase-catalyzed activation of certain N-substituted aryl renal and bladder carcinogens.
Certain carcinogens are thought to induce renal and bladder cancer following metabolic activation. We propose a model system for this activation and provide supporting experimental evidence. This model proposes that renal and bladder carcinogens' entry into the urinary tract is facilitated, that carcinogens are activated by the prostaglandin hydroperoxidase activity of prostaglandin endoperoxide synthetase (PES), and that activation results in covalent binding to nucleic acids which can initiate carcinogenesis. Benzidine and the 5-nitrofuran HMN were shown to inhibit uptake of organic anions and cations, respectively. Carcinogen binding to DNA was dependent upon specific unsaturated fatty acid substrates and prevented by specific inhibitors of PES, i.e., aspirin. Activation with organic peroxides or H(2)O(2) was inhibited by antioxidants but not aspirin. Horseradish peroxidase (HRP) metabolized benzidine but not ANFT. Acetaminophen and the 5-nitrofurans ANFT and HMN prevented PES (14)C-benzidine metabolism. However, only acetaminophen inhibited HRP metabolism of benzidine. The only aerobic metabolism we have observed of 5-nitrofurans is PES-catalyzed. Aspirin (0.5% in the diet) inhibited rat bladder hyperplastic lesions induced by feeding 0.1% or 0.2% FANFT for 6 or 12 weeks. Aspirin reduced bladder prostaglandin synthesis and PES metabolism of FANFT. After one year of an ongoing long-term study, gross examination reveals bladder tumors in 85% of the rats fed 0.2% FANFT and in only 37% of the rats fed FANFT plus 0.5% aspirin.
D000588:Amines / Q000378:metabolism*; D000818:Animals; D001560:Benzidines / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002384:Catalysis; D055598:Chemical Phenomena; D002621:Chemistry; D006735:Horseradish Peroxidase / Q000378:metabolism; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008954:Models, Biological; D009581:Nitrofurans / Q000378:metabolism; D010544:Peroxidases / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*; D014551:Urinary Tract / Q000378:metabolism
D000588:Amines; D001560:Benzidines; D002273:Carcinogens; D009581:Nitrofurans; C029876:benzidine; C022464:prostaglandin hydroperoxidase; D006735:Horseradish Peroxidase; D010544:Peroxidases