Comparative carcinogenicity in a/j mice and metabolism by cultured mouse peripheral lung of n’-nitrosonornicotine 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone, and their analogues

The tumorigenic activities in A/J mouse lung of the tobacco-specific nitrosamines N’-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and their metabolites retaining the nitroso group were studied, and the metabolism of NNN and NNK in cultured mouse peripheral lung was investigated. A total dose of 0.12 mmol of each NNN metabolite was given in 22 i.p. injections to each A/J mouse. Thirty weeks after the last injections, the number of lung tumors per animal induced was NNN, 1.2; 3̍-hydroxy-N’-nitrosonornicotine 0.9; 4̍-hydroxy-N’-nitrosonornicotine, 1.6; and N'-nitrosonornicotine-1 -N-oxide, 0.8. [2’,5̍, 5̍-trideutero]-N’-Nitrosonornicotine, an α-trideutero analogue of NNN, induced 1.5 lung tumors/animal. In cultured mouse peripheral lung, the major metabolic pathways of [2̍-¹⁴C]NNN were 2̍- and 5̍-carbon hydroxylation. Pyridine N-oxidation and N-denitrosation were also observed to a minor extent. These results indicate that 3’ hydroxylation, 4’-hydroxylation, and N-oxidation are not involved in the metabolic activation of NNN in A/J mouse lung. A total dose of 0.10 mmol of NNK induced 37.6 lung tumors/animal. Two of its metabolites, 4-(methylnitrosamino)-1-(3-pyridyl)butan-1 -ol (NNAI; 26.3 tumors/animal) and 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1 -butanone, 3.6 tumors/animal, were less potent than was NNK. A few nasal cavity and liver tumors were also observed in the NNK- and NNAI-treated groups. In cultured peripheral lung, [1-¹⁴C]NNK was rapidly converted to [1-¹⁴C]NNAI, and both of these nitrosamines were metabolized by a-carbon hydroxylation. Radioautography of explants treated with [2̍-¹⁴C]NNN or [1 -¹⁴C]NNK showed higher labeling of the bronchi than of the parenchyma. The results of this study indicate that NNN and NNK can be metabolized by a-carbon hydroxylation in A/J mouse lung where most tumors are observed.