4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific
nitrosamine, induces lung
adenomas in A/J mice following a single intraperitoneal (i.p.) injection. However, inhalation of mainstream cigarette
smoke does not induce or promote NNK-induced lung
tumors in this mouse strain purported to be sensitive to chemically-induced lung
tumorigenesis. The critical events for NNK-induced lung
tumorigenesis in A/J mice is thought to involve
O(6)-methylguanine (O(6)MeG) adduct formation, GC-->AT transitional mispairing, and activation of the K-ras proto-oncogene. The objective of this study was to test the hypothesis that a
smoke-induced shift in NNK metabolism 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
smoke as observed in previous studies. Following 2 h nose-only exposure to mainstream cigarette
smoke (600 mg total suspended particulates/m(3) of air), mice (n=12) were administered 7.5 micromol NNK (10 microCi [5-3H]NNK) by i.p. injection. A control group of 12 mice was
sham-exposed to HEPA-filtered air for 2 h prior to i.p. administration of 7.5 micromol NNK (10 microCi [5-3H]NNK). Exposure to mainstream cigarette
smoke had no effect on total excretion of NNK metabolites in 24 h urine; however, the metabolite pattern was significantly changed. Mice exposed to mainstream cigarette
smoke excreted 25% more
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) than control mice, a statistically significant increase (P<0.0001). Cigarette
smoke exposure significantly reduced alpha-hydroxylation of NNK to potential methylating 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 different in the two groups of mice. The observed reduction in alpha-hydroxylation of NNK to potential methylating species in mainstream cigarette
smoke-exposed A/J mice provides further mechanistic support for earlier studies demonstrating that concurrent inhalation of mainstream cigarette
smoke results in a significant reduction of NNK-induced O(6)MeG adduct formation in lung and liver of A/J mice compared to mice treated only with NNK.