EFFECTS OF PHENETHYL ISOTHIOCYANATE ON THE TISSUE DISTRIBUTION OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE AND METABOLITES IN F344 RATS

Phenethyl isothiocyanate (PEITC), a naturally occurring chemopreventiv e agent, inhibits lung tumor induction in rats by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study, we examined the mechanism of tumor inhibition by determini ng the effects of dietary PEITC on levels of NNK and its metabolites i n various tissues of NNK-treated F344 rats, F344 rats were fed control or PEITC-containing diets (3 mu mol/g diet) before and throughout NNK treatment, To study NNK metabolism and distribution under both shortt erm and chronic NNK/NNK+PEITC treatments, control and PEITC-treated gr oups were divided into four subgroups, Subgroups were treated with eit her a single injection of [5-H-3]NNK (1.76 mg/kg) or a total of 12, 24 , and 36 doses of NNK administered three times/week. After a final inj ection of [5-H-3]NNK in each subgroup, the rats were sacrificed at var ious time intervals, and NNK and its metabolites in lung, liver, nasal mucosa, pancreas, kidney, stomach, and serum were measured, Time-cour se curves for the tissue metabolites were generated, and the areas-und er-the-curves were compared, We observed that lung, liver, and nasal m ucosa, target tissues of NNK carcinogenesis in F344 rats, were also th e tissues that had the highest levels of alpha-hydroxylation metabolit es relative to NNK and its carbonyl reduction metabolite, 4-(methylnit rosamino)-1-(3-pyridyl)-1-butanol (NNAL), The most pronounced effect o f PEITC was a reduction in levels of alpha-hydroxylation metabolites i n most tissues examined (except nasal mucosa), The ratio of alpha-hydr oxylation products to NNK+NNAL in most tissues was decreased by PEITC, indicating that alpha-hydroxylation of NNK/NNAL was inhibited. PEITC did not significantly affect the total levels of NNK and its metabolit es in the lung and most tissues examined, indicating that PEITC does n ot alter the amount of NNK reaching the lung, These results support th e hypothesis that inhibition of NNK-induced lung tumorigenesis by PEIT C is a result of decreased metabolic activation of NNK.