METABOLISM OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDLYL)-1-BUTANONE (NNK) BY HAMSTER, MOUSE AND RAT INTESTINE - RELEVANCE OF SPECIES-DIFFERENCES

We recently demonstrated the metabolism of 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK) in rat intestinal segments, as well as the i nducibility of intestinal NNK metabolism by starvation or acetone trea tment, To improve our understanding of intestinal NNK turnover we have additionally investigated NNK metabolism in isolated perfused jejunal segments from NMRI mice and Syrian golden hamsters, [C-14]NNK (1 mu m ol/L) was metabolized extensively by jejunal segments from female NMRI mice (88.5%) and. female Syrian hamsters (86.4%), whereas in male NMR I mouse segments a slightly lower metabolism (68.8%) was observed, alp ha-Hydroxylation was the predominant metabolic pathway in mice (58% of total metabolism), whereas in female Syrian hamsters N-oxidation acco unted for >50% of the metabolites methylnitrosamino)-1-(3-pyridyl-N-ox ide)-1-butanol 27%, ethylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone 22% of total radioactivity]. Formation of 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanol (NNAL) was low in both species, Total NNK metabolis m in male NMRI mice was increased by starvation to 84.4% and by aceton e treatment to 90.0% of the absorbed radioactivity, This increase was due to an increase in N-oxidation, whereas the amounts of alpha-hydrox ides and NNAL remained unchanged, In female Syrian hamsters acetone tr eatment had only minimal effects upon the metabolite composition, Acet one-treated NMRI mice and Syrian hamsters were additionally gavaged wi th the chemopreventive agent phenethylisothiocyanate (PEITC), In mice this treatment slightly decreased keto acid formation (0.6-fold, P < 0 .05), whereas in hamsters PEITC had no effect, In summary, intestinal metabolism of NNK in rats, mice and hamsters differs in both the exten t of total metabolism (hamsters greater than or equal to mice > rats) and the metabolite composition, indicating major species differences.