METABOLISM AND MUTAGENESIS

新陈代谢和诱变

• 批准号: 6442934
• 负责人: JAMES S. FELTON
• 金额: $ 7.89万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6442934
• 关键词: CHO cells; DNA damage; DNA repair; cell type; chemical carcinogen; clinical research; cytochrome P450; cytotoxicity; electrospray ionization mass spectrometry; food processing /preparation; high performance liquid chromatography; human subject; imidazole; laboratory mouse; laboratory rat; meat; mutagen testing; mutagens; nitrogenous heterocyclic compound; nutrition related neoplasm /cancer; nutrition related tag; sectioning; toxin metabolism; transfection; urinalysis

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.

各种饮食因素与人类的病因有关 癌症包括食物中存在的致癌物质。 在煮熟的肉和 这些已显示出在啮齿动物和非人类中产生肿瘤 灵长类动物。 第1阶段和2阶段的代谢都与 这些杂环胺的诱变激活可能是 与体内的致癌作用有关。 煮熟的肉 杂环胺，2-氨基-1-甲基-6-苯基咪唑[4,5-B]吡啶（PHLP） 在大多数肉类中，已在最高水平上检测到。 遗传毒性活性 细菌和哺乳动物细胞测定中的PHLP以及 啮齿动物肿瘤生物测定中的肿瘤发生，与 其他食物来源的杂环胺，这可能暗示差异 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 这些化合物激活的机制。 代谢和激活 PHLP的pHLP将在啮齿动物和人体组织制剂中进行研究 哺乳动物细胞和整个动物。 各种DNA加合物形成 组织将与这些组织的代谢能力进行比较。 这 代谢激活途径改变对DNA加合物的影响 将评估形成和其他遗传毒性终点。 机制 细菌和 哺乳动物的遗传毒性测定将通过CHO细胞系确定 表达各种水平的P450和共轭酶。 DNA和 蛋白质加合物将被特征在于与PHLP一起使用 代谢物作为暴露的生化标志。 体外代谢 将评估新特征的杂环胺。 这些研究 应提供有关PHLP和其他其他的目标组织特异性的信息 杂环胺，应提供有用的数据外推 对人类的风险。