title: Interactions between methylating and pyridyloxobutylating agents in A/J mouse lungs: implications for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis.
abstract: 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 O(6)-methylguanine (O(6)-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 O(6)-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 O(6)-mG by O(6)-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, O(6)-benzylguanine (O(6)-bG). NNKOAc and O(6)-bG had similar effects on the levels of AMMN-derived O(6)-mG at 4 and 96 h postinjection. This increase in O(6)-mG levels correlated to increased lung tumor multiplicity in animals simultaneously treated with AMMN (0.75 or 1 micromol) and NNKOAc or O(6)-bG. Only NNKOAc significantly increased lung tumor multiplicity at doses of 0.25 or 0.5 micromol 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 O(6)-mG persistence. It is likely that similar interactions are important for the organospecific effects of 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone.
authors.affiliation: Division of Environmental and Occupational Health and Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. peter431@umn.edu
authors.forename: L A
authors.initials: LA
authors.lastname: Peterson
authors.forename: N M
authors.initials: NM
authors.lastname: Thomson
authors.forename: D L
authors.initials: DL
authors.lastname: Crankshaw
authors.forename: E E
authors.initials: EE
authors.lastname: Donaldson
authors.forename: P J
authors.initials: PJ
authors.lastname: Kenney
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects; D004260:DNA Repair; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D009602:Nitrosamines / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000477:Alkylating Agents; D002273:Carcinogens; D009602:Nitrosamines; D011725:Pyridines; C064976:O(6)-benzylguanine; C081510:4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone; C014659:methyl(acetoxymethyl)nitrosamine; D006147:Guanine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C008449:O-(6)-methylguanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D004128:Dimethylnitrosamine