The effect of a 2-h exposure to cigarette smoke on the metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mice

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific ni trosamine, induces lung adenomas in A/J mice following a single intraperito neal. (i.p.) injection. However, inhalation of mainstream cigarette smoke d oes not induce or promote NNK-induced lung tumors in this mouse strain purp orted to be sensitive to chemically-induced lung tumorigenesis. The critica l events for NNK-induced lung tumorigenesis in A/J mice is thought to invol ve O-6-methylguanine (O(6)MeG) adduct formation, GC--> AT transitional misp airing, and activation of the K-ras proto-oncogene. The objective of this s tudy was to test the hypothesis that a smoke-induced shift in NNK metabolis m led to the observed decrease in O(6)MeG adducts in the lung and liver of A/J mice co-administered NNK with a concomitant 2-h exposure to cigarette s moke as observed in previous studies. Following 2 h nose-only exposure to m ainstream cigarette smoke (600 mg total suspended particulates/m(3) of air) , mice (n = 12) were administered 7.5 mu mol NNK (10 mu Ci [5-(3) H]NNK) by i.p. injection. A control group of 12 mice was sham-exposed to HEPA-filter ed air for 2 h prior to i.p. administration of 7.5 mu mol NNK (10 mu Ci [5- H-3]NNK). Exposure to mainstream cigarette smoke had no effect on total exc retion of NNK metabolites in 24 h urine; however, the metabolite pattern wa s significantly changed. Mice exposed to mainstream cigarette smoke excrete d 25% more 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) than contro l mice, a statistically significant increase (P < 0.0001). Cigarette smoke exposure significantly reduced <alpha>-hydroxylation of NNK to potential me thylating species; this is based on the 15% reduction in excretion of the 4 -(3-pyridyl)-4-hydroxybutanoic acid and 42% reduction in excretion of 4-(3- pyridyl)-4-oxobutanoic acid versus control. Detoxication of NNK and NNAL by pyridine-N-oxidation, and glucuronidation of NNAL were not significantly d ifferent in the two groups of mice. The observed reduction in alpha -hydrox ylation of NNK to potential methylating species in mainstream cigarette smo ke-exposed A/J mice provides further mechanistic support for earlier studie s demonstrating that concurrent inhalation of mainstream cigarette smoke re sults in a significant reduction of NNK-induced O-6 MeG adduct formation in lung and Ever of A/J mice compared to mice treated only with NNK. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.