TY - JOUR
T1 - Formation and repair of pyridyloxobutyl DNA adducts and their relationship to tumor yield in A/J mice
AU - Urban, Anna M.
AU - Upadhyaya, Pramod
AU - Cao, Qing
AU - Peterson, Lisa A.
PY - 2012/10/15
Y1 - 2012/10/15
N2 - 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 O 6-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.
AB - 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 O 6-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.
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U2 - 10.1021/tx300245w
DO - 10.1021/tx300245w
M3 - Article
C2 - 22928598
AN - SCOPUS:84867535660
SN - 0893-228X
VL - 25
SP - 2167
EP - 2178
JO - Chemical research in toxicology
JF - Chemical research in toxicology
IS - 10
ER -