METABOLISM AND MUTAGENESIS

多种饮食因素与人类的病因有关。 癌症，包括接触食物中存在的致癌物质。 在熟肉中检测到高度诱变的杂环胺和 这些物质已经被证明在啮齿类动物和非人类身上会产生肿瘤。 灵长类动物。第一阶段和第二阶段的代谢都强烈地牵涉到 这些杂环胺的诱变活性，推测是 与体内的癌变有关。从熟肉中提取的 杂环胺，2-amino-1-methyl-6-phenylimidazo[4，5-b]pyridine(PhlP) 在大多数肉类中检测到的水平最高。遗传毒性活性 PhlP在细菌和哺乳动物细胞检测中的应用 啮齿动物肿瘤生物测定中的肿瘤发生与啮齿动物肿瘤生物测定显著不同 其他食源性杂环胺，可能提示存在差异 激活机制。拟议研究的目标是 评估PhlP和其他杂环胺的代谢并测定 这些化合物的活化机制。新陈代谢和活化 将在啮齿动物和人类组织制剂中研究PhlP的 哺乳动物细胞和整个动物体内。DNA加合物在不同组织中的形成 这些组织将与这些组织的代谢能力进行比较。这个 代谢激活途径改变对DNA加合物的影响 将对形成和对其他遗传毒性终点的影响进行评估。机制 杂环胺在细菌和细菌中的潜在区别效力 哺乳动物的遗传毒性分析将通过使用CHO细胞系来确定 表达不同水平的P450和结合酶。DNA和 蛋白质加合物将与PhlP一起表征为潜在的用途 代谢物作为暴露的生化标志物。阿司匹林的体外代谢 将对新表征的杂环胺进行评估。这些研究 应提供PhlP和其他靶组织特异性的信息 杂环胺，并应提供有用的数据外推 对人类的威胁。

A variety of dietary factors have been implicated in the etiology of human cancers including exposure to carcinogenic substances present in foods. Highly mutagenic heterocyclic amines have been detected in cooked meats and these have been shown to produce tumors in rodents and in nonhuman primates. Both Phase 1 and 2 metabolism have been strongly implicated in the mutagenic activation of these heterocyclic amines and presumably are associated with carcinogenesis in vivo. Of the cooked meat-derived heterocyclic amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP) has been detected at the highest levels in most meats. Genotoxic activity of PhlP in bacterial and mammalian cellular assays, as well as tumorigenesis in rodent tumor bioassays, significantly differs from that of other food-derived heterocyclic amines which may suggest differential mechanisms of activation. The goals of the proposed studies are to evaluate metabolism of PhlP and other heterocyclic amines and to determine the mechanisms of activation of these compounds. Metabolism and activation of PhlP will be studied in rodent and human tissue preparations, in mammalian cells and in whole animals. DNA adduct formation in various tissues will be compared with metabolic capacity of these tissues. The effects of alterations in metabolic activation pathways on DNA adduct formation and on other genotoxic endpoints will be assessed. Mechanisms underlying differential potency of heterocyclic amines in bacterial and mammalian genotoxicity assays will be determined by using CHO cell lines expressing various levels of P450s and conjugation enzymes. DNA and protein adducts will be characterized for potential use along with PhlP metabolites as biochemical markers of exposure. In vitro metabolism of newly characterized heterocyclic amines will be assessed. These studies should provide information on target tissue specificity of PhlP and other heterocyclic amines and should provide useful data for extrapolation of risk to humans.