PANCREAS AND LIVER CARCINOGEN METABOLISM IN TWO SPECIES

这项建议的长期目标是实现对 对化学致癌反应的物种差异。这样的一种 为了评估不同物种对人类的风险，理解是必不可少的。 环境致癌物质，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 致癌物质，特别是对一组有效的亚硝胺 对仓鼠有胰腺致癌作用，但对大鼠无致癌作用。这些亚硝胺 由两个结构类别组成，其中N-亚硝基(2-氧丙基)胺 (MOP)和N-亚硝基双(2-氧丙基)胺(BOP)是典型的例子。 具体的目的是为了了解物种的差异 对这些化合物的反应。到目前为止完成的工作表明， 肝脏在激活这些亚硝胺方面起着至关重要的作用。使用计算机 以模拟为指导的MOP在仓鼠体内的药代动力学模型 肝细胞正在构建中。新陈代谢的平行测量和 碱洗脱法评估的DNA损伤正被用来鉴定 导致基因毒性中间体的代谢途径。我们会作出努力 确定这些中间体的结构，合成它们或 它们的前体，并在培养和整个动物中测试它们。一个 在老鼠身上也进行了类似的研究，以期确定差异。 对这两个物种胰腺的不同反应至关重要。 最后，建议将同样的方法应用于国际收支类 化合物，可能有也可能没有共同的致癌机制 和拖把班一起。

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.