MECHANISMS OF CARCINOGENESIS AND MUTAGENESIS

目前人们认为，很高比例的人类癌症导致 暴露在环境化学物质中。人们对此知之甚少 环境中致癌化学物质的能力 在人类身上制造肿瘤的实验动物。这种不确定性的部分原因 结果是缺乏适当的数据作为推断的基础 在动物研究中使用的高剂量降至低水平 环境。物种间的差异反应是一种复合反应 有问题。因为大多数致癌物被认为是通过一种 与DNA产生突变的相互作用，了解DNA的类型 导致突变的加合物和加合物的形成机制 形成或修复可能是理解相关因素的重要因素 冒着风险。在本提案中，有几种方法可以识别 N-亚硝基化合物产生的前诱变DNA加合物和简单 将使用鼠伤寒沙门氏菌中的烷化剂。这些 涉及特定加合物与两种检测的突变的相关性 在正向和反向分析中，它们是：1.加合物的鉴定 形成与突变体相同的剂量反应，2.加合物的鉴定 由相同诱变剂量的不同诱变剂以相似的水平形成 生成相同的加合物。3.调查不同环境因素的影响 细菌DNA修复系统对突变和加合物水平的影响。 用诱变剂处理细菌，在液体中培养或生长 悬浮液及前后突变体和DNA加合物的测定 孵化过程。此外，诱变剂将与裸露的DNA和加合物反应 与上述结果进行比较，以确定渗透的效果 或在内收水平上快速修复。上述所有实验的结果 将用于建立诱变前加合物的效力指数，并 将诱变作用分解为其组成部分的过程。此外，诱变 关于一大群亚硝胺的体外代谢的数据将是 以这样的方式确定和表达之间的相关性 诱变和致癌能力(如果存在)可能会变得明显。 更多的研究将试图确定一些细菌DNA的特征 根据基材、辅因和特性修复系统。

It is currently believed that a high percentage of human cancer results from exposure to environmental chemicals. Little is known about the abilities of the environmental chemicals which are carcinogens in experimental animals to produce tumors in humans. Part of this uncertainty results from the lack of suitable data on which to base extrapolations from the high doses used in animal studies to the low levels found in the environment. Differential response among species is a compounding problem. As most carcinogens are believed to initiate carcinogenesis via a mutation-producing interactions with DNA, knowledge of the types of DNA adducts which lead to mutations and the mechanisms by which the adducts are formed or repaired could be important in understanding factors associated with risk. In this proposal several methods of identifying premutagenic-DNA adducts produced by N-nitroso compounds and simple alkylating agents in Salmonella typhimurium will be employed. These involve the correlations of particular adducts with mutations assayed both in forward and reversion assays and are: 1. identification of adducts formed with the same dose response as mutants, 2. identification of adducts formed at similar levels by equimutagenic doses of different mutagens which generate the same adducts. 3. investigation of the effects of different bacterial DNA repair systems on mutations and adduct levels and 4. treatment of bacteria with mutagens, incubation or outgrowth in liquid suspension, and determination of mutants and DNA adducts before and after the incubation. Also mutagens will be reacted with naked DNA and adducts compared with those obtained above, to determine the effects of permeation or rapid repair on adduct levels. Results of all of the above experiments will be used to establish a potency index of premutagenic adducts and to dissect mutagenesis into its component processes. In addition, mutagenesis and data on in vitro metabolism of a large group of nitrosamines will be determined and expressed in such a manner that correlations between mutagenic and carcinogenic potencies (if they exist) may become evident. Additional studies will attempt to characterize some of the bacterial DNA repair systems with respect ot substrates, cofactors and specificities.