Effect of aspirin and indomethacin on the formation of benzo(a)pyrene-induced pulmonary adenomas and DNA adducts in A/HeJ mice

• Published in: Cancer research (Chicago, Ill.) Vol. 43; no. 10; pp. 4762 - 4767
• Main Authors: ADRIAENSSENS, P. I, KANDIAH SIVARAJAH, BOORMAN, G. A, ELING, T. E, ANDERSON, M. W
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.1983
• Subjects: Adenoma - chemically induced; Animals; Aspirin - pharmacology; Benzo(a)pyrene; Benzopyrenes - metabolism; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Chromatography, High Pressure Liquid; Cyclooxygenase Inhibitors; DNA - metabolism; Female; Indomethacin - pharmacology; Liver - metabolism; Lung Neoplasms - chemically induced; Medical sciences; Mice; Mice, Inbred Strains; Rats; Stomach - metabolism; Tumors; Hydrocarbon; Respiratory disease; Rodentia; Prostaglandin antagonist; Polycyclic aromatic compound; Bronchopulmonary; Activity metabolism relation; Carcinogen; Vertebrata; Mammalia; Mouse; Animal; DNA; Metabolic activation; Mechanism of action; Experimental tumor; Molecular adduct
• ISSN: 0008-5472; 1538-7445

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.