DETERMINANTS OF DIETARY RISK OF HETEROCYCLIC AMINE

富含蛋白质食品的热处理和热解以及标准 美国烹饪方法，如烤、煎和烧烤肉类 诱导强效致突变和致癌杂环的形成 胺类。 这些相同的化合物在多个器官部位产生肿瘤 小鼠和大鼠。 非人类灵长类动物喂食其中一种杂环胺 经过很短的潜伏期后就发展成了肝癌。 此外， 流行病学研究表明肉类消费与 人类癌症。 由于这些发现，确定 这些诱变剂/致癌物是否会导致人类癌症发病率。 该提案将尝试通过以下方式实现这一目标：1) 识别和量化 饮食中接触这些杂环胺； 2）探索实践 通过防止诱变剂形成来减少暴露的方法； 3） 通过 DNA 分析了解这些化合物的慢性毒理学 长期结合、细胞遗传学损伤和突变效应 喂养啮齿动物； 4）研究人类个体的重要性 通过评估 CHO 细胞修复和代谢的差异 DNA 修复和代谢激活的遗传差异； 5） 以理解为目标表征重要的代谢途径 由这些引起的组织特异性致癌的性质 啮齿动物和非人灵长类动物中的杂环胺； 6）理解 与低剂量暴露相关的生物剂量测定 摄入这些强效诱变剂； 7）由此生成的主题数据 癌症风险评估文献中的项目和数据。 在 这项研究的结论，细胞遗传学损伤的基本机制， 这些化合物引起的代谢和DNA加合会更多 彻底了解了。 此外，基于暴露的风险评估， 将开发剂量测定法和药代动力学。

Heat processing and pyrolysis of protein-rich foods along with standard American cooking practices such as broiling, frying and barbecuing of meats induce the formation of potent mutagenic and carcinogenic heterocyclic amines. These same compounds produced tumors at multiple organ sites in both mice and rats. Nonhuman primates fed one of these heterocyclic amines have developed hepatocarcinomas after a very short latency. Furthermore, epidemiology studies suggest a good correlation of meat consumption with cancer in humans. Because of these findings, it is important to determine whether these mutagens/carcinogens contribute to human cancer incidence. This proposal will attempt to do so by: 1) Identifying and quantifying dietary exposure to these heterocyclic amines; 2) Exploring practical methods of reducing exposure by preventing mutagen formation; 3) Understanding the chronic toxicology of these compounds by analysis of DNA binding, cytogenetic damage and mutational effects following long-term feeding of rodents; 4) Studying the importance of individual human differences in repair and metabolism by assessment in CHO cells having genetic differences in DNA repair and metabolic activation; 5) Characterizing important metabolic pathways with the goal of understanding the nature of the tissue-specific carcinogenesis induced by these heterocyclic amines in rodents and in nonhuman primates; 6) Understanding the biological dosimetry related to the low-dose exposures from the ingestion of these potent mutagens; 7) Subjecting data generated from this project and data from the literature to cancer-risk assessment. At the conclusion of this study, basic mechanisms of cytogenetic damage, metabolism and DNA adduction caused by these compounds will be more thoroughly understood. In addition, a risk assessment based on exposure, dosimetry, and pharmacokinetics will be developed.