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Interactions between Methylating and Pyridyloxobutylating Agents in A/J Mouse Lungs

Implications for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced Lung Tumorigenesis¹

Division of Environmental and Occupational Health and Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455

The tobacco-specific nitrosamine, 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone, is activated to lung DNA methylating and pyridyloxobutylating intermediates. It is likely that both pathways play a role in lung tumor initiation by this nitrosamine. Previous studies indicated that O⁶-methylguanine (O⁶-mG) persistence is critical for lung tumor formation in A/J mice. The model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc), enhanced the tumorigenic activity of a model methylating agent, acetoxymethylmethylnitrosamine (AMMN), presumably by increasing O⁶-mG persistence in lung DNA. We have been testing the hypothesis that the pyridyloxobutylation pathway increases the mutagenic activity of the DNA methylation pathway by preventing the repair of O⁶-mG by O⁶-alkylguanine-DNA alkyltransferase (AGT). In this study, we report that NNKOAc depletes AGT in lungs but not livers of A/J mice. The consequences of AGT depletion by NNKOAc were then compared with those observed with a known AGT inhibitor, O⁶-benzylguanine (O⁶-bG). NNKOAc and O⁶-bG had similar effects on the levels of AMMN-derived O⁶-mG at 4 and 96 h postinjection. This increase in O⁶-mG levels correlated to increased lung tumor multiplicity in animals simultaneously treated with AMMN (0.75 or 1 µmol) and NNKOAc or O⁶-bG. Only NNKOAc significantly increased lung tumor multiplicity at doses of 0.25 or 0.5 µmol AMMN. The results from these studies indicate that the pyridyloxobutylating agent, NNKOAc, can influence the tumorigenic activity of methylating agents in two ways. At low AMMN doses, the increase in tumor multiplicity is dominated by the additive tumorigenic properties of AMMN and NNKOAc. At higher AMMN doses, NNKOAc appears to enhance the tumorigenic activity of AMMN through enhanced depletion of the repair protein, AGT, leading to increased O⁶-mG persistence. It is likely that similar interactions are important for the organospecific effects of 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone.

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