Toxicological Sciences, Vol 47, 33-39, Copyright © 1999 by Society of Toxicology
BG Brown, CJ Chang, PH Ayres, CK Lee and DJ Doolittle
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 tobacco smoke has
not induced or promoted tumors in these mice. NNK-induced lung
tumorigenesis is thought to involve O6-methylguanine (O6MeG) formation,
leading to GC-->AT transitional mispairing and an activation of the
K-ras proto-oncogene in the A/J mouse. NNK can be metabolized by several
different cytochromes P450, resulting in a number of metabolites. Formation
of the promutagenic DNA adduct O6MeG is believed to require metabolic
activation of NNK by cytochrome P450-mediated alpha-hydroxylation of the
methylene group adjacent to the N-nitroso nitrogen to yield the unstable
intermediate, methanediazohydroxide. Nicotine, cotinine (the major
metabolite of nicotine), and aqueous cigarette tar extract (ACTE) have all
been shown to effectively inhibit metabolic activation of NNK to its
mutagenic form, most likely due to competitive inhibition of the cytochrome
P450 enzymes involved in alpha- hydroxylation of NNK. The objective of the
current study was to monitor the effects of cotinine and cigarette smoke
(CS) on the formation of O6MeG in target tissues of mice during the acute
phase of NNK treatment. To test the effect of cotinine, mature female A/J
mice received a single intraperitoneal injection of NNK (0, 2.5, 5, 7.5, or
10 mumole/mouse) with cotinine administered at a total dose of 50
mumole/mouse in 3 separate i.p. injections, administered 30 min before,
immediately after, and 30 min after NNK treatment. To test the effect of
whole smoke exposure on NNK-related O6MeG formation, mice were exposed to
smoke generated from Kentucky 1R4F reference cigarettes at 0, 0.4, 0.6, or
0.8 mg wet total particulate matter/liter (WTPM/L) for 2 h, with a single
i.p. injection of NNK (0, 3.75, or 7.5 mumole/mouse) midway through the
exposure. Cigarette smoke alone failed to yield detectable levels of O6MeG.
The number of O6MeG adducts following i.p. injection of NNK was
significantly (p < 0.05) reduced in both lung and liver by cotinine and
by cigarette smoke exposure. Our results demonstrate that NNK-induced O6MeG
DNA adducts in A/J mice are significantly reduced when NNK is administered
together with either cotinine, the major metabolite of nicotine, or the
parental complex mixture, cigarette smoke.
ARTICLES
The effect of cotinine or cigarette smoke co-administration on the formation of O6-methylguanine adducts in the lung and liver of A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) [published erratum appears in Toxicol Sci 1999 Jul;50(1):153]
Research & Development Department, R. J. Reynolds Tobacco Co., Winston- Salem, North Carolina 27102, USA.
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