DNA adduct formation of heterocyclic amine isomers in rats

描述(申请人提供)：经常食用熟肉会增加患结肠癌和乳癌的风险；然而，导致这种风险的病因仍有待阐明。关于致癌物的报告，第11版，国家毒理学计划，得出结论，在烤肉中出现的杂环芳香胺(HAAs)被合理地预期为人类致癌物质。许多流行病学研究表明，HAAs是这些癌症的特定病原体。然而，已报道的饮食因素和遗传多态数据之间的关联并不能证实特定的化学暴露与癌症发生之间的关系。此外，在熟制的烤肉和其他未定性的HAAs中，由于这类化学物质的致突变性，具有特征性的HAAs所占比例不到30%。最近，我们发现了动物致癌物2-氨基-1-7-二甲基咪唑[4，5-g]喹恶啉(7-MeIgQx)，它是2-氨基-3，8-二甲基咪唑[4，5-f]喹恶啉(8-MeIQx)的异构体。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化学标记物来区分处于不同风险水平的个体，以评估HAAs构成的癌症风险。鉴于熟牛肉中形成的高浓度7-MeIgQx与8-MeIQx或2-amino-1-methyl-6-phenylimidazo[4，5-b]pyridine(PhIP)有关，这两种HaA被认为与饮食相关的癌症有关，我们假设7-MeIgQx是HAAs总体遗传毒性负担和癌症风险的重要贡献者。本应用的目的是为7-MeIgQx在体外进行生物活化和在大鼠体内与DNA结合的能力提供初步的毒理学数据。我们将使用高灵敏的加速器质谱学方法在体内测量7-MeIgQx的DNA加合物产率，并将其与8-MeIQx的产率进行比较。理由是，这些初步研究产生的数据将根据致癌物结合指数，与8-MeIQx相比，初步评估7-MeIgQx的致癌潜力。这项拟议的研究与美国国立卫生研究院的公共卫生使命有关：具体目标1和2将建立7-MeIgQx与其致癌异构体8-MeIQx之间遗传毒性潜力的毒理学数据。拟议的一种新发现的HAA的体内DNA结合研究是一种创新的方法，可以快速、临时地评估7-MeIgQx的致癌潜力，它产生的熟牛肉数量比8-MeIQx和PhIP更多。这一发现意义重大，因为7-MeIgQx的代谢物和DNA加合物可以作为接触这类饮食致癌物和进行风险评估的生物标志物。公共卫生相关性：拟议的研究将提供对新发现的杂环芳胺(HAA)2-氨基-1，7-二甲基咪唑[4，5-g]喹恶啉(7-MeIgQx)致癌潜力的临时估计。HAAs被认为是人类致癌物质，而7-MeIgQx是熟肉中形成的质量最丰富的HAA。这项研究将使我们能够确定7-MeIgQx与饮食中存在的其他HA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.