PANCREAS AND LIVER CARCINOGEN METABOLISM IN TWO SPECIES

本提案的长期目标是， 化学致癌反应的物种差异。 这样的 为了评估各种危险对人类的危害， 环境致癌物，特别是为了使 从动物研究中推断到人类的任何可靠性。 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，特别是一组亚硝胺， 对仓鼠胰腺致癌物，但对大鼠无致癌作用。 这些亚硝胺 由两种结构类型组成，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。 具体目标是为了了解物种的差异， 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中起重要作用。 利用计算机 以模拟为指导MOP在仓鼠体内代谢动力学模型 正在构建肝细胞。 代谢的平行测量， DNA损伤，如碱性洗脱评估，正在被用来识别 导致遗传毒性中间体的代谢途径。 将努力 确定这些中间体的结构，合成它们， 它们的前体，并在培养物和整个动物中测试它们。 一 建议在大鼠中进行类似的研究，以确定差异 这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， 化合物，可能有或可能没有共同的致癌机制 在MOP类。

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.