Formation and Repair of Pyridyloxobutyl DNA Adducts and Their Relationship to Tumor Yield in A/J Mice

• Published in: Chemical research in toxicology 2012-10, Vol.25 (10), p.2167-2178
• Main Authors: Urban, Anna M, Upadhyaya, Pramod, Cao, Qing, Peterson, Lisa A
• Format: Article
• Language: English
• Subjects: Animals; Carcinogens - metabolism; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; DNA Adducts - metabolism; Enzyme Inhibitors - pharmacology; Female; Guanine - analogs & derivatives; Guanine - pharmacology; Lung - metabolism; Lung - pathology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mutagens - metabolism; Nitrosamines - metabolism; O-Methylguanine-DNA Methyltransferase - antagonists & inhibitors; O-Methylguanine-DNA Methyltransferase - metabolism; Pyridines - metabolism
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx300245w

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), O 2-[4–3-(pyridyl)-4-oxobut-1-yl]-cytodine (O 2-pobC), O 2-[4–3-(pyridyl)-4-oxobut-1yl]thymidine (O 2-pobdT), and O 6-[4–3-(pyridyl)-4-oxobut-1-yl]-2′-deoxyguanosine (O 6-pobdG). Mutagenic O 6-pobdG is thought to contribute to the tumorigenic properties of the pyridyloxobutylation pathway. It is repaired by O 6-alkylguanine-DNA alkyltransferase (AGT). To explore the role of O 6-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, O 6-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 O 6-pobdG and did not increase tumor formation. Three pyridyloxobutyl DNA adducts, 7-pobG, O 2-pobdT, and O 6-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.