Role of O6-alkylguanine in nitrosamine-induced cancers

O6-烷基鸟嘌呤在亚硝胺诱发的癌症中的作用

• 批准号: 7225272
• 负责人: Lisa A Peterson
• 金额: $ 24.65万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225272
• 关键词: A/J Mouse; Abbreviations; Address; Affect; Butanones; Cancer Patient; Carcinogens; Class; DNA; DNA Adducts; DNA Damage; DNA Repair; DNA alkyltransferase; Drug Metabolic Detoxication; Epidemiologic Studies; Equilibrium; Genetic Predisposition to Disease; Genotype; Goals; Grant; Guanine; Human; Individual; Investigation; Laboratories; Link; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic Pathway; Modeling; Molecular; N' -nitrosonornicotine; N-methylacetamide-oxotremorine M; Nitrosamines; Nucleotide Excision Repair; O(6)-Methylguanine-DNA Methyltransferase; O(6)-benzylguanine; Pathway interactions; Phenotype; Predisposition; Property; Proteins; Range; Relative (related person); Research Personnel; Risk; Role; Smoker; Smoking; Staging; Testing; Tobacco; Tobacco-Associated Carcinogen; Translating; Variant; adduct; base; cancer risk; gene environment interaction; programs; repaired

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.

描述（由申请人提供）：烟草特有的亚硝胺 NNK 和 NNN 在实验室中具有致癌性，并且是潜在的人类致癌物。 NNN 代谢为 DNA 吡啶氧丁基化剂，而 NNK 代谢为 DNA 吡啶氧丁基化和甲基化中间体。 DNA 的吡啶氧丁基化会导致多种 DNA 加合物的形成，其中之一是 O6-[4-氧代-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 变体修复 O6-pobG 的能力存在显着差异，这表明修复能力降低的个体患烟草相关癌症的风险可能增加。然而，目前尚不清楚 O6-pobG 在吡啶氧丁基化亚硝胺的致突变和致癌特性中的总体作用。本次资助研究的中心假设是，O6-pobG 在未修复时对烟草特有的亚硝胺、NNK 和 NNN 的诱变和致癌活性有显着贡献。我们计划通过追求以下具体目标来检验我们的中心假设：1）确定 O6-pobG 的形成和持久性是否与 A/J 小鼠中 NNN 和 NNKOAc 的肺部致癌特性有关。 2) 人类肝脏通过 AGT 修复相对于 O6-mG 加合物的庞大 O6-烷基鸟嘌呤加合物的能力。 3)确定其他修复途径参与诱变O6-pobG的整体修复，并确定这些途径是否影响吡啶氧丁基化剂的诱变特性。总的来说，这些目标将确定 O6-pobG 的形成和修复在吡啶氧丁基化亚硝胺的致突变和致癌特性中的重要性。这些研究将为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是否会增加患烟草相关癌症的风险。