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It has been proposed thatO  6-methylguanine DNA methyltransferase (MGMT) gene silencing in premalignant lesions and cancers of the lung might result in the acquisition of a ‘mutator’ phenotype. Previously, however, we found thatMgmt  −/−mouse DNA failed to show an increase in spontaneous mutations. We thus hypothesized that only during exposure to specific environmental carcinogens would the consequences of MGMT deficiency become evident. Metabolism of the tobacco-derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) generates alkylating species that can react with theO  6position of deoxyguanine, thereby yielding substrates for MGMT-mediated repair. To investigate how MGMT might regulate the mutational effects of NNK,Mgmt  −/−mice were crossed with alacI-based transgenic reporter line (Big Blue™) thus enabling an assessment of thein vivomutagenic effects of this agent. We observed the induction of a complex spectrum of NNK-dependentlacImutations in both control andMgmt  −/−tissues, but only a trend in the mutant frequency increases that could be attributed to MGMT deficiency. The mutational spectra of NNK-treatedMgmt  −/−lungs revealed an increase in the absolute number of G:C to A:T changes accompanied by a shift in these from CpG to GpG sites, consistent with an SN1 alkylation mechanism. In keeping with the high levels of MGMT expressed in the liver, more pronounced mutagenic effects and greater differences inO  6position of deoxyguanosine adduct levels following NNK were observed inMgmt  −/−versus wild-type mice. Extrapolating to humans, MGMT-deficient cells would likely exhibit an increased mutational burden, but only following exposures to specific environmental mutagens such as NNK.

carcinogenesis

Mgmt               deficiency alters the               in vivo               mutational spectrum of tissues exposed to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)