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

Chem Biol Interact. 2001 Nov 28;138(2):125-35. doi: 10.1016/s0009-2797(01)00265-4.


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.

MeSH terms

  • Animals
  • Carcinogens / administration & dosage
  • Carcinogens / metabolism*
  • Carcinogens / toxicity
  • Chromatography, High Pressure Liquid
  • DNA / drug effects
  • DNA / metabolism
  • DNA Adducts
  • Drug Interactions
  • Female
  • Guanine / analogs & derivatives*
  • Guanine / metabolism
  • Hydroxylation / drug effects
  • Injections, Intraperitoneal
  • Liver / drug effects
  • Liver / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Mice
  • Mice, Inbred Strains
  • Nitrosamines / administration & dosage
  • Nitrosamines / metabolism*
  • Nitrosamines / toxicity
  • Tobacco Smoke Pollution / adverse effects*


  • Carcinogens
  • DNA Adducts
  • Nitrosamines
  • Tobacco Smoke Pollution
  • Guanine
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • DNA
  • O-(6)-methylguanine