Rat pulmonary microsomal cytochrome P-450 enzymes involved in the activation of procarcinogens.
Rat lung microsomal cytochrome P-450 (P-450) enzymes have been characterized with regard to their catalytic specificities towards activation of several procarcinogens to genotoxic metabolites in Salmonella typhimurium TA1535/pSK1002. We first examined the roles of rat liver microsomal P-450 enzymes in the activation of benzo[a]pyrene and its 7,8-diol enantiomers to genotoxic products, and found that P-450 1A1 is a major catalyst for the activation of these potential procarcinogens in rat livers. Using lung microsomes isolated from rats treated with various P-450 inducers we obtained evidence that at least three P-450 enzymes are involved in the activation of several procarcinogens. Immunoinhibition studies support the view that benzo[a]pyrene and its 7,8-diol derivatives, other dihydrodiol derivatives of polycyclic aromatic hydrocarbons, and 3-amino-1-methyl-5H-pyrido[4,3-b]indole are activated to genotoxins mainly by rat P-450 1A1, which is inducible in rat lungs by 5,6-benzoflavone and the polychlorinated biphenyl mixture Aroclor 1254. Activation of 2-amino-3,5-dimethylimidazo[4,5-f]quinoline and 2-amino-3-methylimidazo[4,5-f]quinoline may be catalyzed by another P-450 enzyme because the activities were not induced by treatment with 5,6-benzoflavone or Aroclor 1254. The observation that both activities were inhibited by antibodies raised against P-450 1A2 and by 7,8-benzoflavone suggests a role for an enzyme of P-450 1A family, probably P-450 1A2, in rat lung microsomes. The activation of aflatoxin B1 and sterigmatocystin appears to be catalyzed by other P-450 enzyme(s) rather than the P-450 1A family as judged by the different responses of activities to the P-450 inducers and the specific antibodies in rat lung microsomes. Interestingly, lung microsomal activation of several procarcinogens was found to be suppressed in rats treated with isosafrole and pregnenolone 16 alpha-carbonitrile. Thus, the results support the roles of different P-450 enzymes in the activation of procarcinogens in rat lung microsomes.
D000348:Aflatoxins / Q000494:pharmacology; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000502:physiology*; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D066298:In Vitro Techniques; D008168:Lung / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D011284:Pregnenolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013014:SOS Response, Genetics; D012451:Safrole / Q000494:pharmacology; D013241:Sterigmatocystin / Q000494:pharmacology; D019324:beta-Naphthoflavone
D000348:Aflatoxins; D001571:Benzoflavones; D002273:Carcinogens; D013241:Sterigmatocystin; D019324:beta-Naphthoflavone; D011284:Pregnenolone; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D012451:Safrole; C015959:isosafrole; D010634:Phenobarbital