DNA adduct formation of heterocyclic amine isomers in rats

大鼠杂环胺异构体 DNA 加合物的形成

• 批准号: 7584872
• 负责人: Robert J. Turesky
• 金额: $ 6.07万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7584872
• 关键词: 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; Accounting; Animals; Binding; Biological Assay; Biological Markers; Carcinogens; Cessation of life; Chemical Exposure; Chemicals; Chemoprevention; Colon; Colorectal; Consumption; Cytochrome P450; DNA; DNA Adduction; DNA Adducts; DNA Binding; Data; Detection; Diesel Exhaust; Diet; Diet Habits; Dietary Factors; Dose; Enzyme Kinetics; Enzymes; Epidemiologic Studies; Exposure to; Genetic; Genetic Polymorphism; Goals; Health; Heterocyclic Amines; Human; In Vitro; Individual; Isomerism; Label; Lead; Link; Liver; Liver Microsomes; Malignant Neoplasms; Measures; Meat; Methods; Mission; Mole the mammal; Morbidity - disease rate; Mutagenesis; Mutagens; National Toxicology Program; Nucleotides; Organ; Pilot Projects; Prevention strategy; Primary Prevention; Public Health; Quinoxalines; Rattus; Recombinants; Relative (related person); Reporting; Research; Risk; Risk Assessment; Risk Factors; Role; Skeleton; Structure; Tissues; Tobacco smoke; United States; Urine; accelerator mass spectrometry; adduct; base; beef; cancer risk; carcinogenesis; cooking; dosage; genotoxicity; heterocyclic aromatic amines; in vivo; indexing; innovation; male; malignant breast neoplasm; mortality; oxidation; public health relevance; pyridine; red meat consumption

DESCRIPTION (provided by applicant): The frequent consumption of meats cooked well-done leads to an increased risk for colon and breast cancer; however, the etiological agents responsible for this risk remain to be elucidated. The Report on Carcinogens, Eleventh Edition, National Toxicology Program, concluded that heterocyclic aromatic amines (HAAs), which arise in grilled meats, are reasonably anticipated to be human carcinogens. Many epidemiological studies have implicated HAAs as specific etiological agents in these cancers. However, the reported associations of dietary factors and genetic polymorphism data can not confirm the relationships between specific chemical exposures and carcinogenesis. Moreover, the characterized HAAs account for less than 30% of the mutagenicity attributed to this class of chemicals in well-done grilled meats and other uncharacterized HAAs are present. Recently, we discovered 2-amino-1-7-dimethylimidazo[4,5-g]quinoxaline (7-MeIgQx), an isomer of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), a potent animal carcinogen. 7-MeIgQx, is the most mass-abundant, genotoxic HAA formed in grilled beef; however, its carcinogenic potential is unknown. Our long-term goal is to assess the cancer risk posed by HAAs, by establishing chemical markers that may distinguish individuals at different levels of risk. Given the high concentrations of 7-MeIgQx formed in cooked beef in relationship to 8-MeIQx or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), two HAAs that are believed to contribute to dietary-related cancers, we hypothesize that 7-MeIgQx is a significant contributor to the overall genotoxic burden and cancer risk posed by HAAs. The objective of this application is to provide preliminary toxicological data on the capacity of 7-MeIgQx to undergo bioactivation in vitro and bind to DNA in vivo in the rat. We will use highly sensitive accelerator mass spectrometry methods to measure DNA adduct yields of 7-MeIgQx in vivo and compare the yields to those of 8-MeIQx. The rationale is that data generated from these pilot studies will provide a preliminary assessment of the carcinogenic potential of 7-MeIgQx in comparison to 8-MeIQx, based on the carcinogen binding index. This proposed research is relevant to NIH's mission on public health: specific aims 1 and 2 will establish toxicological data on the genotoxic potential of 7-MeIgQx in relationship to its carcinogenic isomer, 8-MeIQx. The proposed DNA binding study in vivo of a newly discovered HAA is an innovative approach to provide a rapid, provisional assessment of the carcinogenic potential of 7-MeIgQx, which arises cooked beef in greater quantities than 8-MeIQx and PhIP. This discovery is highly significant since metabolites and DNA adducts of 7- MeIgQx could serve as biomarkers of exposure and risk assessment to this class of dietary carcinogens. PUBLIC HEALTH RELEVANCE: The proposed study will provide a provisional estimate of the carcinogenic potential of a newly discovered heterocyclic aromatic amine (HAA), 2-amino-1,7-dimethylimidazo[4,5-g]quinoxaline (7-MeIgQx). HAAs are believed to be human carcinogens and 7-MeIgQx is the most mass-abundant HAA formed in cooked meat. The research will allow us to determine the health risk of 7-MeIgQx in relationship to other HAAs present in the diet.

描述（由申请人提供）：经常食用煮熟的肉类会增加患结肠癌和乳腺癌的风险；然而，造成这种风险的病因仍有待阐明。国家毒理学计划第十一版致癌物报告得出的结论是，烤肉中产生的杂环芳香胺 (HAA) 被合理地预期为人类致癌物。许多流行病学研究表明 HAA 是这些癌症的特定病因。然而，报道的饮食因素和遗传多态性数据的关联并不能证实特定化学物质暴露与致癌之间的关系。此外，在全熟烤肉中，已表征的 HAA 占此类化学物质致突变性的不到 30%，并且还存在其他未表征的 HAA。最近，我们发现了2-氨基-1-7-二甲基咪唑并[4,5-g]喹喔啉（7-MeIgQx），它是2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（8-MeIQx）的异构体，是一种强效动物致癌物。 7-MeIgQx，是烤牛肉中形成的质量最丰富、具有遗传毒性的 HAA；然而，其致癌潜力尚不清楚。我们的长期目标是通过建立可以区分不同风险水平个体的化学标记来评估 HAA 造成的癌症风险。鉴于煮熟的牛肉中形成的高浓度 7-MeIgQx 与 8-MeIQx 或 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶 (PhIP) 相关，这两种 HAA 被认为会导致与饮食相关的癌症，我们假设 7-MeIgQx 是 HAA 造成的总体遗传毒性负担和癌症风险的重要贡献者。本申请的目的是提供有关 7-MeIgQx 在体外进行生物活化并在大鼠体内与 DNA 结合的能力的初步毒理学数据。我们将使用高灵敏度的加速器质谱方法来测量 7-MeIgQx 体内 DNA 加合物的产率，并将其与 8-MeIQx 的产率进行比较。理由是，这些试点研究产生的数据将根据致癌物结合指数，对 7-MeIgQx 与 8-MeIQx 相比的致癌潜力进行初步评估。这项拟议的研究与 NIH 的公共卫生使命相关：具体目标 1 和 2 将建立 7-MeIgQx 与其致癌异构体 8-MeIQx 相关的遗传毒性潜力的毒理学数据。拟议的新发现的 HAA 体内 DNA 结合研究是一种创新方法，可对 7-MeIgQx 的致癌潜力进行快速、临时评估，熟牛肉中 7-MeIgQx 的致癌量高于 8-MeIQx 和 PhIP。这一发现非常重要，因为 7-MeIgQx 的代谢物和 DNA 加合物可以作为此类膳食致癌物暴露和风险评估的生物标志物。公共健康相关性：拟议的研究将对新发现的杂环芳香胺 (HAA)、2-氨基-1,7-二甲基咪唑并[4,5-g]喹喔啉 (7-MeIgQx) 的致癌潜力进行临时估计。 HAA 被认为是人类致癌物，7-MeIgQx 是熟肉中形成的最丰富的 HAA。这项研究将使我们能够确定 7-MeIgQx 与饮食中存在的其他 HAA 的健康风险。