PANCREAS AND LIVER CARCINOGEN METABOLISM IN TWO SPECIES

两个物种的胰腺和肝脏致癌物代谢

• 批准号: 3169339
• 负责人: THOMAS J CURPHEY
• 金额: $ 12.57万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-09-01 至 1988-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3169339
• 关键词: DNA repair; autoradiography; biotransformation; carcinogen testing; cellular oncology; chemical binding; chemical carcinogenesis; computer simulation; environment related neoplasm /cancer; high performance liquid chromatography; liver metabolism; liver neoplasms; mass spectrometry; mutagen testing; nitrosamines; pancreas neoplasms; species difference; tissue /cell culture

The long-term objective of this proposal is to achieve an understanding of species differences in response to chemical carcinogenesis. Such an understanding is essential in order to assess the risk to man of a variety of environmental carcinogens and, in particular, in order to make extrapolations from animal studies to man with any degree of reliability. The proposal focuses on nitrosamines, an ubiquitous class of environmental carcinogens and, in particular, on a group of nitrosamines which are potent pancreatic carcinogens for hamster, but not for rat. These nitrosamines consist of two structural classes, of which N-nitroso(2-oxopropyl)amine (MOP) and N-nitrosobis(2-oxopropyl)amine (BOP) are typical examples. Specific aims are directed toward understanding the species difference in response to these compounds. Work accomplished to date has suggested an essential role for liver in activating these nitrosamines. Using computer simulation as a guide, a pharmacokinetic model of MOP metabolism in hamster hepatocytes is being constructed. Parallel measurements of metabolism and DNA damage, as assessed by alkaline elution, are being used to identify metabolic routes leading to genotoxic intermediates. Efforts will be made to determine the structure of these intermediates, to synthesize them or their precursors, and to test them in culture and in whole animals. A similar study in rats is proposed, with a view to identifying differences crucial to the differing response of pancreas of the two species. Finally, it is proposed to apply the same approaches to the BOP class of compounds, which may or may not have mechanisms of carcinogenesis in common with the MOP class.

该提案的长期目标是让人们了解 对化学致癌反应的物种差异。 这样一个 为了评估对人类的各种风险，理解是至关重要的 环境致癌物，特别是为了使 从动物研究到人类的推断具有任何程度的可靠性。 该提案的重点是亚硝胺，这是一种普遍存在的环境污染物 致癌物，特别是一组强效亚硝胺 对仓鼠来说是胰腺致癌物，但对大鼠则不然。 这些亚硝胺 由两个结构类别组成，其中N-亚硝基(2-氧代丙基)胺 (MOP) 和 N-亚硝基双(2-氧代丙基)胺 (BOP) 是典型的例子。 具体目标是了解物种差异 对这些化合物的反应。 迄今为止完成的工作表明 肝脏在激活这些亚硝胺方面发挥着重要作用。 使用电脑 以模拟为指导，建立仓鼠MOP代谢的药代动力学模型 肝细胞正在构建。 代谢的并行测量和 通过碱性洗脱评估的 DNA 损伤被用来识别 导致遗传毒性中间体的代谢途径。 将会做出努力 确定这些中间体的结构，合成它们或 他们的前身，并在培养物和整个动物中测试它们。 一个 提议在大鼠中进行类似的研究，以期找出差异 对两个物种胰腺的不同反应至关重要。 最后，建议将相同的方法应用于 BOP 类别 可能具有或不具有共同致癌机制的化合物 与 MOP 类。