MECHANISMS OF CARCINOGENESIS AND MUTAGENESIS

目前认为，很高比例的人类癌症是由 暴露在环境化学物质中。 很少有人知道的 环境化学物质的致癌能力， 实验动物在人类身上产生肿瘤。 这种不确定性的一部分 由于缺乏适当的数据， 动物研究中使用的高剂量与 环境 物种之间的差异反应是一种复合 问题. 由于大多数致癌物质被认为是通过一种 与DNA的相互作用，DNA类型的知识 导致突变的加合物以及加合物被 形成或修复可能是重要的，在理解相关因素 有风险。 在本建议中， 由N-亚硝基化合物和简单的 将使用鼠伤寒沙门氏菌中的烷化剂。 这些 涉及特定加合物与突变的相关性， 在正向和反向测定中，并且是：1.加合物鉴定 形成与突变体相同的剂量反应，2.加合物鉴定 由等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.调查不同的影响 细菌DNA修复系统的突变和加合物水平和4. 用诱变剂处理细菌，在液体中培养或生长 悬浮液，并测定前后的突变体和DNA加合物 孵化 诱变剂也将与裸DNA和加合物反应 与上面获得的那些进行比较，以确定渗透的效果 或加合物水平的快速修复。 上述所有实验的结果 将用于建立致突变前加合物的效价指数， 将诱变分解成其组成过程。 此外，诱变 和数据在体外代谢的一大群亚硝胺将 以这样的方式确定和表达， 致突变和致癌效力（如果存在）可能变得明显。 进一步的研究将试图描述一些细菌DNA的特征， 修复系统方面的底物，辅因子和特异性。

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.