METABOLISM OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE (NNK) INISOLATED RAT LUNG AND LIVER

The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1 -butanone (NNK) is a strong lung carcinogen in all species tested. To elicit its tumorigenic effects NNK requires metabolic activation which is ne supposed to take place via a-hydroxylation, whereas N-oxidation is suggested to be a detoxification pathway. The differences in the o rgan specific metabolism of NNK may be crucial for the organotropy in NNK-induced carcinogenesis. Therefore, metabolism of NNK was investiga ted in the target organ lung and in liver of Fischer 344 (F344) rats u sing the model of isolated pet-fused organs. High activity to metaboli ze 35 nM [5-H-3]NNK was observed in both perfused organs. NNK was elim inated by liver substantially faster (clearance 6.9 +/- 1.6 ml/min, ha lf-life 14.6 +/- 1.2 min) than by lung (clearance 2.1 +/- 0.5 ml/min, half-life 47.9 +/- 7.4 min). When the clearance is calculated for a gr am of organ or for metabolically active cell forms, the risk with resp ect to carcinogenic mechanisms was higher in lung than in liver. The m etabolism of NNK in liver yielded the two products Of NNK alpha-hydrox ylation, the 4-oxo-4-(3-pyridyl)-butyric acid (keto acid) and 4-hydrox y-4-(3-pyridyl)-butyric acid (hydroxy acid). in lung, the major metabo lite of NNK was ethylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NN K-N-oxide). Substantial amounts of metabolites formed from methyl hydr oxylation of NNK, which is one of the two possible pathways of alpha-h ydroxylation, were detected in lung but not in liver perfusion. Format ion of these metabolites (4-oxo-4-(3-pyridyl)-butanol (keto alcohol), and 3-hydroxy-4-(3-pyridyl)-butanol (diol) can give rise to pyridyloxo butylating of DNA. When isolated rat livers were perfused with 150 mu M NNK, equal to a dosage which is sufficient to induce liver tumors in rat, glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was increased when compared to the concentration of 35 nhl NNK . Nevertheless, the main part of NNK was also transformed via alpha-hy droxylation for this high concentration of NNK.