METABOLISM AND MUTAGENESIS

多种饮食因素已被牵连在人类的病因学 癌症，包括接触食物中的致癌物质。 在熟肉中检测到高致突变性杂环胺， 这些已被证明在啮齿动物和非人类中产生肿瘤， 灵长类动物 1期和2期代谢均强烈涉及 这些杂环胺的致突变活性， 与体内致癌作用有关。 来自熟肉的 杂环胺，2-氨基-1-甲基-6-苯基咪唑并[4，5-B]吡啶（PhIP） 在大多数肉类中检测到的含量最高。 遗传毒性活性 在细菌和哺乳动物细胞测定中的PhlP，以及 在啮齿动物肿瘤生物测定中的肿瘤发生，与 其他食源性杂环胺，可能提示差异 激活机制。 拟议研究的目标是 评估PhlP和其他杂环胺的代谢，并确定 这些化合物的激活机制。 代谢和活化 将在啮齿动物和人体组织制备物中研究PhlP， 哺乳动物细胞和整个动物。 DNA加合物的形成 将这些组织与这些组织的代谢能力进行比较。 的 代谢活化途径的改变对DNA加合物的影响 形成和其他遗传毒性终点进行评估。 机制 杂环胺在细菌和 哺乳动物遗传毒性试验将使用CHO细胞系进行测定 表达不同水平的P450和结合酶。 DNA和 蛋白质加合物将被表征为与PhlP一起沿着潜在使用 代谢物作为暴露的生化标志物。 的体外代谢 将评估新表征的杂环胺。 这些研究 应提供关于PhlP靶组织特异性和其他 杂环胺，并应提供有用的数据外推 对人类的风险。

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.