title: Formation and repair of pyridyloxobutyl DNA adducts and their relationship to tumor yield in A/J mice.
abstract: The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a known human carcinogen. It generates methyl and pyridyloxobutyl DNA adducts. The role of the methyl DNA adducts has been well-established in the tumorigenic properties of NNK. However, the role of the pyridyloxobutyl DNA adducts is unclear. Four pyridyloxobutyl DNA adducts have been characterized: 7-[4-3-(pyridyl)-4-oxobut-1-yl]guanine (7-pobG), O²-[4-3-(pyridyl)-4-oxobut-1-yl]-cytodine (O²-pobC), O²-[4-3-(pyridyl)-4-oxobut-1yl]thymidine (O²-pobdT), and O⁶-[4-3-(pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (O⁶-pobdG). Mutagenic O⁶-pobdG is thought to contribute to the tumorigenic properties of the pyridyloxobutylation pathway. It is repaired by O⁶-alkylguanine-DNA alkyltransferase (AGT). To explore the role of O⁶-pobdG formation and repair in the tumorigenic properties of NNK, A/J mice were given single or multiple doses of the model pyridyloxobutylating agent 4-(acetoxymethyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) in the presence or absence of the AGT depletor, O⁶-benzylguanine. Levels of the four pyridyloxobutyl DNA adducts were measured in the lung at 8, 48, or 96 h following treatment and compared to the lung tumorigenic activity of these treatments. AGT depletion had only a modest effect on the levels of O⁶-pobdG and did not increase tumor formation. Three pyridyloxobutyl DNA adducts, 7-pobG, O²-pobdT, and O⁶-pobdG, persisted in lung DNA at significant levels for up to 96 h post-treatment, suggesting that all three adducts may contribute to the tumorigenic properties of NNK.
authors.affiliation: Division of Environmental Health Sciences and ‡Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Urban
authors.forename: Pramod
authors.initials: P
authors.lastname: Upadhyaya
authors.forename: Qing
authors.initials: Q
authors.lastname: Cao
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Peterson
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009153:Mutagens / Q000378:metabolism*; D009602:Nitrosamines / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D009153:Mutagens; D009602:Nitrosamines; C473029:O(6)-(4-oxo-4-(3-pyridyl)butyl)guanine; D011725:Pyridines; C064976:O(6)-benzylguanine; C081510:4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone; D006147:Guanine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D019853:O(6)-Methylguanine-DNA Methyltransferase; D003849:Deoxyguanosine