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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.
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1983
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Chemoprevention StrategyLung InflammationTotal DoseLast InjectionsMolecular PharmacologyReactive Nitrogen SpecieRespiratory ToxicologyPulmonary PharmacologyToxicologyRadiation OncologyCancer ResearchBiochemistryOncogenic AgentComparative CarcinogenicityMetabolomicsExperimental ToxicologyPharmacologyLung CancerInhalation ToxicologyA/j MiceMajor Metabolic PathwaysBronchial NeoplasmMedicineNitrosative Stress
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; 3′-hydroxy- N ′-nitrosonornicotine, 0.9; 4′-hydroxy- N ′-nitrosonornicotine, 1.6; and N ′-nitrosonornicotine-1- N -oxide, 0.8. [2′,5′,5′- 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 [2′-14C]NNN were 2′- and 5′-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 α-carbon hydroxylation. Radioautography of explants treated with [2′-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 α-carbon hydroxylation in A/J mouse lung where most tumors are observed.