Metabolism and tissue distribution of tobacco-specific N-nitrosamines in the marmoset monkey (Callithrix jacchus)

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Abstract
Three male marmoset monkeys (Callithrix jacchus) were injected i.v. with the tobacco-specific carcinogen [2'-14C]N'-nitrosonornicotine (NNN) (20.3 μmol/kg body weight) or [carbonyl-14C]4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (18.8 or 420 μmol/kg body weight). They were sacrificed 4 h later. Tissue distribution was studied in two monkeys by whole-body autoradiography and by computer-assisted densitometric analysis of the autoradiograms. The autoradiograms showed a high level of radioactivity in the liver, nasal mucosa, kidneys, melanin of the eyes, hair-follicles of the skin and in the ceruminous ear glands of the monkeys. Total level of radioactivity was 5.7 times higher in the liver of the [carbonyl-14C]NNK-injected monkey than in that of [2'-14C]NNN-injected monkey. Washing the sections with trichloroacetic acid and organic solvents selectively removed free metabolites leaving metabolites bound to cellular macromolecules. Level of bound metabolites was 1.5 times higher in the nasal mucosa than in the liver of the [2'-14C]NNN monkey. Levels of bound metabolites were similar in the liver of NNN-and NNK-treated monkeys. The results indicate that the liver and nasal mucosa of C. jacchus can activate NNN and NNK to alkylating species. Unbound metabolites present in the liver, lung, kidneys, eye, blood and urine were extracted and separated by h.p.l.c. Hydroxylation of the carbons α to the N-nitroso group of NNN were the major metabolic pathways. Unmetabolized NNN was the major radioactive component in the liver, lung, eye and blood. Reduction of the carbonyl of NNK yields 4-(methylnitrosamino)-1-(3-pyridyl)butan-1-ol (NNAI). NNAI was present in all tissues analyzed and was the major radioactive component in the eye and stomach lumen. It was also excreted in the urine. NNK and NNAI were metabolized by α-carbon hydroxylation. These results suggest that in C. jacchus, NNN, NNK and NNAI are activated to alkylating species by α-carbon hydroxylation. In the third monkey injected with NNK, DNA methylation was observed in the liver and nasal mucosa but not in the lung and kidneys.