DNA adduct formation of heterocyclic amine isomers in rats

描述（由申请人提供）：经常食用煮熟的肉类会导致结肠癌和乳腺癌的风险增加;然而，导致这种风险的病原体仍有待阐明。致癌物报告，第十一版，国家毒理学计划，得出的结论是，杂环芳香胺（哈斯），其中产生的烤肉，是合理的预期是人类致癌物。许多流行病学研究表明，哈斯是这些癌症的特异性病原体。然而，膳食因素和遗传多态性数据的相关性报道不能证实特定化学品暴露与致癌之间的关系。此外，表征的哈斯占全熟烤肉中该类化学品致突变性的不到30%，并且存在其他未表征的哈斯。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，是一种强有力的动物致癌物。7-MeIgQx是烤牛肉中形成的质量最丰富的遗传毒性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的个体的化学标志物来评估哈斯造成的癌症风险。鉴于熟牛肉中形成的7-MeIgQx与8-MeIQx或2-氨基-1-甲基-6-苯基咪唑[4，5-B]吡啶（PhIP）（两种被认为会导致饮食相关癌症的哈斯）相关，我们假设7-MeIgQx是哈斯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7-MeIgQx在大鼠体内进行体外生物活化和与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法来测量7-MeIgQx在体内的DNA加合物的产率，并将产率与8-MeIQx的产率进行比较。基本原理是，根据致癌物结合指数，这些初步研究生成的数据将提供7-MeIgQx与8-MeIQx相比的致癌潜力的初步评估。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的遗传毒性潜力的毒理学数据。新发现的HAA的拟议体内DNA结合研究是一种创新方法，可快速、临时评估7-MeIgQx的致癌潜力，7-MeIgQx可使煮熟的牛肉产生比8-MeIQx和PhIP更大的量。这一发现非常重要，因为7- MeIgQx的代谢物和DNA加合物可以作为这类膳食致癌物暴露和风险评估的生物标志物。公共卫生相关性：拟议的研究将提供一个新发现的杂环芳香胺（HAA），2-氨基-1，7-二甲基咪唑[4，5-g]喹喔啉（7-MeIgQx）的致癌潜力的临时估计。哈斯被认为是人类致癌物，7-MeIgQx是熟肉中形成的最大量的HAA。这项研究将使我们能够确定7-MeIgQx与饮食中存在的其他哈斯的健康风险。

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.