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 high-performance liquid chromatography. The results of the wholebody 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 high-performance 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 alpha-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 14CO2 or 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.

[1]  E. Brittebo,et al.  Tissue-specificity of N-nitrosodibutylamine metabolism in Sprague-Dawley rats. , 1982, Chemico-biological interactions.

[2]  J. Adams,et al.  Carcinogenic tobacco-specific N-nitrosamines in snuff and in the saliva of snuff dippers. , 1981, Cancer research.

[3]  E. Brittebo,et al.  Sites of metabolism of N-nitrosodiethylamine in mice. , 1981, Chemico-biological interactions.

[4]  S. Hecht,et al.  Carcinogenicity, metabolism and DNA binding of the tobacco specific nitrosamine, 4-(methylnitrosamino)-1-3(3-pyridyl)-1-butanone (NNK) , 1981 .

[5]  S. Hecht,et al.  Comprehensive analysis of urinary metabolites of N'-nitrosonornicotine. , 1981, Carcinogenesis.

[6]  E. Brittebo,et al.  Formation of tissue-bound N'-nitrosonornicotine metabolites by the target tissues of Sprague-Dawley and Fisher rats. , 1981, Carcinogenesis.

[7]  E. Brittebo,et al.  Extrahepatic sites of metabolism of N-nitrosopyrrolidine in mice and rats. , 1981, Xenobiotica; the fate of foreign compounds in biological systems.

[8]  S. Hecht,et al.  Metabolism in the F344 rat of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco-specific carcinogen. , 1980, Cancer research.

[9]  S. Hecht,et al.  Comparative carcinogenicity in F344 rats of the tobacco-specific nitrosamines, N'-nitrosonornicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone. , 1980, Cancer research.

[10]  H. Tjälve,et al.  Studies on the distribution and metabolism of 14C-dimethylnitrosamine in foetal and young mice. , 2009, Acta pharmacologica et toxicologica.

[11]  H. Ruf,et al.  Binding of nitrosamines to cytochrome P-450 of liver microsomes. , 1979, Chemico-biological interactions.

[12]  S. Hecht,et al.  Assessment of tobacco-specific N-nitrosamines in tobacco products. , 1979, Cancer research.

[13]  S. Hecht,et al.  Metabolic α-Hydroxylation of the Tobacco-specific Carcinogen, N′-Nitrosonornicotine , 1978 .

[14]  H. Tjälve,et al.  The distribution of [14C]dimethylnitrosamine in mice. Autoradiographic studies in mice with inhibited and noninhibited dimethylnitrosamine metabolism and a comparison with the distribution of [14C]formaldehyde. , 1978, Toxicology and applied pharmacology.

[15]  S. Hecht,et al.  Tobacco-specific nitrosamines: formation from nicotine in vitro and during tobacco curing and carcinogenicity in strain A mice. , 1978, Journal of the National Cancer Institute.

[16]  H. W. Taylor,et al.  Carcinogenicity of N'-nitrosonornicotine in Sprague-Dawley rats. , 1976, Journal of the National Cancer Institute.

[17]  E. Wynder,et al.  A study of tobacco carcinogenesis. XIV. Effects of N'-nitrosonornicotine and N'-nitrosonanabasine in rats. , 1975, Journal of the National Cancer Institute.

[18]  B. Brodie,et al.  The gastric secretion of drugs: a pH partition hypothesis. , 1957, The Journal of pharmacology and experimental therapeutics.