EFFECTS OF DIETARY-FAT CONTENT ON THE METABOLISM OF NNK AND ON DNA METHYLATION INDUCED BY NNK

The available data support the concept that high-fat diets increase cy tochrome P-450 activities in the liver, leading to increased rates of carcinogen metabolism and, in some instances, DNA adduct formation. Th erefore we investigated whether a high-fat diet can also influence DNA methylation by the tobacco-specific nitrosamine 4-(methylnitrosamino) -1-(3-pyridyl)-1-butanone (NNK) in the lungs of rats. Male F344 rats w ere fed a regular AIN-76A low-fat (5% corn oil) or AIN-76A high-fat (2 3.5% corn oil) diet. After three weeks on this dietary regimen, the an imals were injected subcutaneously once daily for four days with NNK a t 0.39 mmol/kg body wt. Groups of rats were sacrificed 4 and 24 hours after the last NNK administration; livers and lungs were excised for D NA isolation. We found that the high-fat diet significantly enhanced t he formation of O-6-methylguanine (O-6-mGua) in the rat lung four hour s (p < 0.01) after the last carcinogen administration. This may, in pa rt, account for our previous finding in regard to the enhancing effect of the high-fat diet on NNK-induced lung carcinogenesis. There was no effect on O-6-mGua or 7-mGua in the rat liver at either time point. T o further elucidate the enhancing effect of the high-fat diet on DNA m ethylation by NNK in the lung, we determined its effect on the in vitr o and in vivo metabolism of NNK. The in vitro data indicated that diet ary fat has no measurable effect on liver and lung microsomal mixed-fu nction oxidase in catalyzing the metabolic activation of NNK. The resu lts of the metabolism study of NNK in vivo appear to be consistent wit h the in vitro finding, in that fat had no effect on the excretion pat tern of NNK or on the distribution pattern of its urinary metabolites. It is apparent that the enhancing effect of the high-fat diet on O-6- mGua in the lung of rats that was measured four hours after NNK inject ion requires future investigations.