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 chemopreventive 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 determining the effects of dietary PEITC on levels of NNK and its metabolites in various tissues of NNK-treated F344 rats. F344 rats were fed control or PEITC-containing diets (3 mumol/g diet) before and throughout NNK treatment. To study NNK metabolism and distribution under both short-term and chronic NNK/NNK+PEITC treatments, control and PEITC-treated groups were divided into four subgroups. Subgroups were treated with either a single injection of [5-3H]NNK (1.76 mg/kg) or a total of 12, 24, and 36 doses of NNK administered three times/week. After a final injection of [5-3H]NNK in each subgroup, the rats were sacrificed at various time intervals, and NNK and its metabolites in lung, liver, nasal mucosa, pancreas, kidney, stomach, and serum were measured. Time-course curves for the tissue metabolites were generated, and the areas-under-the-curves were compared. We observed that lung, liver, and nasal mucosa, target tissues of NNK carcinogenesis in F344 rats, were also the tissues that had the highest levels of alpha-hydroxylation metabolites relative to NNK and its carbonyl reduction metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). The most pronounced effect of PEITC was a reduction in levels of alpha-hydroxylation metabolites in most tissues examined (except nasal mucosa). The ratio of alpha-hydroxylation 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 metabolites in the lung and most tissues examined, indicating that PEITC does not alter the amount of NNK reaching the lung. These results support the hypothesis that inhibition of NNK-induced lung tumorigenesis by PEITC is a result of decreased metabolic activation of NNK.

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