Division of Environmental Health Sciences and ‡Masonic Cancer Center, University of Minnesota , Minneapolis, Minnesota 55455, USA.
Chem Res Toxicol. 2012 Oct 15;25(10):2167-78. doi: 10.1021/tx300245w. Epub 2012 Sep 13.
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.
亚硝胺 4-(甲基亚硝氨基)-1-(3-吡啶基)-1-丁酮（NNK）是一种已知的人类致癌物。它会产生甲基和吡啶氧丁基 DNA 加合物。甲基 DNA 加合物在 NNK 的致癌特性中已经得到了很好的证实。然而，吡啶氧丁基 DNA 加合物的作用尚不清楚。已经鉴定出四种吡啶氧丁基 DNA 加合物：7-[4-3-(吡啶基)-4-氧代丁基]-鸟嘌呤（7-pobG）、O²-[4-3-(吡啶基)-4-氧代丁基]-胞嘧啶（O²-pobC）、O²-[4-3-(吡啶基)-4-氧代丁基]-胸腺嘧啶（O²-pobdT）和 O⁶-[4-3-(吡啶基)-4-氧代丁基]-2'-脱氧鸟嘌呤（O⁶-pobdG）。具有致突变性的 O⁶-pobdG 被认为是吡啶氧丁基化途径致癌特性的贡献者。它由 O⁶-烷基鸟嘌呤-DNA 烷基转移酶（AGT）修复。为了探索 O⁶-pobdG 形成和修复在 NNK 致癌特性中的作用，A/J 小鼠在存在或不存在 AGT 耗尽剂 O⁶-苄基鸟嘌呤的情况下，单次或多次给予模型吡啶氧丁基化试剂 4-(乙酰氧基甲基-亚硝氨基）-1-(3-吡啶基）-1-丁酮（NNKOAc）。在处理后 8、48 或 96 小时测量肺中的四种吡啶氧丁基 DNA 加合物水平，并将这些处理的肺肿瘤形成活性进行比较。AGT 耗尽对 O⁶-pobdG 的水平仅有适度影响，并且不会增加肿瘤形成。三种吡啶氧丁基 DNA 加合物，7-pobG、O²-pobdT 和 O⁶-pobdG，在处理后长达 96 小时的时间内仍在肺 DNA 中保持显著水平，这表明所有三种加合物都可能对 NNK 的致癌特性做出贡献。
