Prostaglandin H synthase-catalyzed activation of benzidine: a model to assess pharmacologic intervention of the initiation of chemical carcinogenesis.
Carcinogens which cause cancers in tissues distal to their entry are thought to require metabolic activation before covalent binding to macromolecules. The hydroperoxidase component of prostaglandin H synthase (PHS) activates certain carcinogens and a model describing this process is presented. The procarcinogen benzidine was used to identify sites at which microsomal PHS-catalyzed binding might be inhibited by pharmacologic agents. Activation of benzidine was determined by assessing free radical cation formation and covalent binding to protein. Reduction of benzidine diimine to diamine was also assessed. This study provides the first demonstration of inhibition of PHS-activated benzidine binding by propylthiouracil, methimazole, MK447, vitamin C and phenidone. The agents tested identified the following sites at which PHS-catalyzed binding of benzidine can be prevented: 1) inhibition of generation of the peroxide cosubstrate for benzidine oxidation; 2) inhibition of prostaglandin hydroperoxidase; 3) reduction of oxidized intermediate(s) to the parent compound; and 4) conjugation of the activated intermediate(s). This study provides a basis for further investigations of the pharmacologic intervention of chemical carcinogenesis.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology; D001560:Benzidines / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D008956:Models, Chemical; D010544:Peroxidases / Q000378:metabolism; D011441:Propylthiouracil / Q000494:pharmacology; D011449:Prostaglandin Endoperoxides / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011463:Prostaglandins H / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011817:Rabbits; D013268:Stimulation, Chemical
D001095:Arachidonic Acids; D001560:Benzidines; D002273:Carcinogens; D011449:Prostaglandin Endoperoxides; D011463:Prostaglandins H; D011720:Pyrazoles; D002084:Butylated Hydroxytoluene; D016718:Arachidonic Acid; C029876:benzidine; D008713:Methimazole; C013753:2-aminomethyl-4-t-butyl-6-iodophenol; D011441:Propylthiouracil; C022464:prostaglandin hydroperoxidase; D010544:Peroxidases; D011451:Prostaglandin-Endoperoxide Synthases; C015429:phenidone; D001205:Ascorbic Acid; D007213:Indomethacin