Effect of aspirin and indomethacin on the formation of benzo(a)pyrene-induced pulmonary adenomas and DNA adducts in A/HeJ mice.
Previous results in various in vitro systems suggest that prostaglandin endoperoxide synthetase (PES) could serve as either an alternative or an additional enzyme to the cytochrome P-450-dependent monooxygenases for the formation of mutagenic, cell-transforming, and DNA-binding metabolites of carcinogens. To test this hypothesis in vivo, we examined the effect of PES inhibitors on benzo(a)pyrene (BP)-induced pulmonary adenoma and BP metabolite:DNA adduct formation in A/HeJ mice. Animals were treated with a dosage regimen of aspirin which inhibited PES but had no effect on the cytochrome P-450-dependent oxidation of 7,8-dihydrodihydroxybenzo(a)pyrene. Aspirin did not significantly alter the number of pulmonary adenomas per mouse at either dose of BP (6.0 and 3.0 mg per mouse, administered twice, 2 weeks apart). In addition, aspirin treatment did not depress the in vivo formation of BP metabolite:DNA adducts in lung or liver at either dose of BP (6.0 and 0.06 mg/mouse). The lower dose of BP was used in the adduct study to assess the effect of aspirin at a more environmental exposure level of BP. Treatment with indomethacin, another PES inhibitor, also did not reduce the pulmonary BP metabolite:DNA adduct levels. The failure of PES inhibitors to reduce the number of pulmonary adenomas and BP metabolite:DNA adduct levels suggests that cooxidation of BP during prostaglandin biosynthesis may not play a significant role in BP-induced pulmonary adenomas.
D000236:Adenoma / Q000139:chemically induced*; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors; D004247:DNA / Q000378:metabolism*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced*; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats
D001580:Benzopyrenes; D016861:Cyclooxygenase Inhibitors; D001564:Benzo(a)pyrene; D004247:DNA; D001241:Aspirin; D007213:Indomethacin