Role of O6-alkylguanine in nitrosamine-induced cancers

描述（由申请人提供）：烟草特异性亚硝胺，NNK和NNN，在实验室中具有致癌性，是潜在的人类致癌物。NNN代谢为DNA吡啶氧基丁基化剂，而NNK代谢为DNA吡啶氧基丁基化和甲基化中间体。DNA的吡啶氧羧丁基化会形成多种DNA加合物，其中一种是O6-[4-氧-4-（3-吡啶基）丁基]鸟嘌呤（O6- pobg）。我们之前的研究表明，这种诱变加合物是由o6 -烷基鸟嘌呤- dna烷基转移酶（AGT）修复的。人类AGT变体在修复O6-pobG的能力上存在很大差异，这表明修复能力降低的个体患烟草相关癌症的风险可能会增加。然而，目前尚不清楚O6-pobG在吡啶氧基丁基化亚硝胺的致突变性和致癌性中的总体作用。本基金研究的中心假设是，O6-pobG在未修复的情况下，对烟草特异性亚硝胺（NNK和NNN）的致突变和致癌活性起着重要作用。我们计划通过追求以下具体目标来验证我们的中心假设：1)确定在A/J小鼠中，O6-pobG的形成和持久性是否与NNN和NNKOAc的肺部致癌特性有关。2)通过AGT对人类肝脏相对于O6-mG加合物修复大体积o6 -烷基鸟嘌呤加合物的能力进行表型分析。3)确定其他修复途径参与致突变性O6-pobG的整体修复，并确定这些途径是否影响吡啶氧脱丁基化剂的致突变性。总的来说，这些目标将确定O6-pobG的形成和修复在吡啶氧代丁基化亚硝胺的致突变性和致癌性中的重要性。这些研究将为一项分子流行病学研究奠定基础，以确定无法修复这种诱变加合物的个体患烟草相关癌症的风险是否增加。

DESCRIPTION (provided by applicant): Tobacco-specific nitrosamines, NNK and NNN, are carcinogenic in laboratory and are potential human carcinogens. NNN is metabolized to a DNA pyridyloxobutylating agent whereas NNK is metabolized to both DNA pyridyloxobutylating and methylating intermediates. Pyridyloxobutylation of DNA results in the formation of a variety of DNA adducts, one of which is O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6-pobG). Our previous studies indicate that this mutagenic adduct is repaired by O6-alkylguanine-DNA alkyltransferase (AGT). Human AGT variants differ substantially in their ability to repair O6-pobG, suggesting that individuals with reduced repair capacity may be at increased risk of tobacco-related cancers. However, it is unclear what the overall role O6-pobG makes in the mutagenic and carcinogenic properties of pyridyloxobutylating nitrosamines. The central hypothesis under investigation in this grant is that O6-pobG contributes significantly to the mutagenic and carcinogenic activity of the tobacco-specific nitrosamines, NNK and NNN, when not repaired. We plan to test our central hypothesis by pursuing the following specific aims: 1) Determine if O6-pobG formation and persistence are linked to the pulmonary carcinogenic properties of NNN and NNKOAc in A/J mice. 2) Phenotype human livers for their ability to repair bulky O6-alkylguanine adducts relative to O6-mG adducts by AGT. 3) Determine the involvement of other repair pathways in the overall repair of the mutagenic O6-pobG and determine whether these pathways affect the mutagenic properties of pyridyloxobutylating agents. Collectively, these aims will establish the importance of formation and repair of O6-pobG in the mutagenic and carcinogenic properties of pyridyloxobutylating nitrosamines. These studies will set the stage for a molecular epidemiological study to determine whether individuals who are unable to repair this mutagenic adduct are at increased risk of tobacco-related cancers.