Tissue Distribution of the Tobacco-specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and Its Metabolites in F344 Rats

The tissue distribution of the tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the F344 rat was studied by whole-body autoradiography and highperformance liquid chromatography. The results of the whole-body autoradiography experiments indicate that the substance is able to freely cross biological membranes and reach all tissues of the body. A high level of tissue-bound metabolites occurred in the mucosa of the ethmoturbinates, in the lung, and the liver, which are the targets for the carcinogenicity of NNK in F344 rats. However, tissue-bound radioactivity was also present in non-target tissues such as the lateral nasal gland (Steno's gland), the tracheal mucosa, and the mucosa of the nasopharyngeal duct. A high level of unbound radioactivity occurred in the preputial gland, submaxillary and adrenal glands, and the urinary and gastrointestinal systems. High localization of unbound radioactivity was observed in the stomach lumen not only after p.o. but also after i.v. administration of NNK. Analysis of extracts of the stomach contents by highperformance liquid chromatography indicated that, due to their basicity, NNK and its metabolites were trapped in the gastric juice and later reabsorbed from the intestinal tract. Analysis of unbound metabolites in various tissues and in the urine after i.v. or p.o. administration of [carbonyl-¹⁴C]NNK indicated metabolism and excretion of products resulting from ±-carbon hydroxylation, carbonyl reduction, and pyridine N-oxidation of NNK. After p.o. administration of [¹⁴CH₃]NNK, 47% of the dose was recovered as ¹⁴CO₂. [carbonyl- ¹⁴C]NNK, however, was not metabolized to ¹⁴CO₂. Levels of in vitro metabolism of [¹⁴CH₃]-NNK to ¹⁴CO₂or incorporation of radioactivity into the acid-insoluble material after incubation with [carbonyl-¹⁴C]NNK were the highest in the nasal mucosa. Thus, the high activity of NNK-activating enzymes present in the nasal cavity is apparently an important factor in the etiology of NNK-induced neuroepitheliomas. In vitro autoradiography experiments showed that NNK is metabolized in the mucosa of the ethmoturbinates, the lung, and the liver, suggesting that the tumors are induced by metabolites formed locally in the target tissues. In the lung, the labeling was higher in the bronchial tree than in the lung parenchyma.