EFFECT OF ASPIRIN AND INDOMETHACIN ON THE FORMATION OF BENZO(A)PYRENE-INDUCED PULMONARY ADENOMAS AND DNA ADDUCTS IN A/HEJ MICE

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (10) , 4762-4767
Abstract
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, the effect was examined 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/mouse, administered twice, 2 wk 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.