EFFECTS OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS ON OXIDATIVE PATHWAYS IN A/J MICE

The tobacco-specific N-nitrosamine, NNK, is a potent carcinogen in laboratory animals. The authors have shown previously that NNK-induced lung tumorigenesis in A/J mice can be reduced significantly by certain nonsteroidal antiinflammatory drugs (NSAIDs), such as sulindac, ibuprofen, or piroxicam treatments. In this study, the authors investigated whether NSAIDs could reduce NNK-induced oxidative DNA damage and/or inhibit endogenous lipid peroxidation, or prostaglandin E(2) (PGE(2)) synthesis in A/J mice. In the first experiment, A/J mice were gavaged with NNK (112 mu mol/kg b. w.) three times a week while being maintained on a diet to which either ibuprofen (263 mg/kg diet), naproxen (230 mg/kg), sulindac (123 mg/kg), piroxicam (25 mg/kg), indomethacin (5 mg/kg), or no NSAIDs had been added. Levels of 8-OH-dG in the DNA of lung and liver were measured by high-performance liquid chromatography with electron capture detector. Treatment with NSAIDs had no significant effects on the endogenous or NNK-induced formation of 8-OH-dG in the lung of the mice. In a second experiment, after treatment of A/J mice with NSAIDs for 2 weeks, lipid peroxidation was assayed by determining thiobarbituric acid-reactive substances (TBA-RS) in lung tissues, and prostaglandin E(2) levels were measured in plasma by an enzyme immunoassay. Treatments with some NSAIDs lowered the levels of lipid peroxidation and plasma levels of PGE(2) below basal levels. Taken together, these results suggest that the inhibition of NNK-induced lung tumorigenesis by NSAIDs is more likely related to an inhibition of prostaglandin synthesis than to a direct inhibition of lipid peroxidation or oxidative DNA damage induced by NNK.