CARCINOGENESIS--HIGHLY REACTIVE NITROSAMINES

这项建议的根本和根本目标是决心 环境中普遍存在的烷基乙醇的作用机制 亚硝胺，特别是N-亚硝酸钠二乙醇胺Ndela被激活 最终致癌物质，以及阐明阿尔法-α- 亚硝胺、醛和相关化合物可能在这一过程中发挥作用。 将使用化学、生物化学和生物实验来测试 与β-亚硝胺活化有关的MAN假说 乙醇。这些假说是：1)酒精脱氢酶介导 氧化成活性α-亚硝胺醛；2)磺基转移酶 催化硫化反应生成反应性3-烷基-1，2，3-烷基-1，2，3- 恶二唑阳离子；以及3)涉及生产的链缩短 活性亲电体或简单的烷基亚硝胺，它们是 细胞色素p-450介导α-羟基化的底物。这个 具体目标是：1)确定与生物相关的 α-亚硝胺醛、1，2，3-恶二唑的化学 以及N-亚硝基脱氢吗啉及其环氧化物，依次揭示了 这些活性化合物的可能反应可能是从 它们在体外修饰DNA。我们将继续阐明其结构 主要的DNA和蛋白质。2)α-亚硝胺的测定 醛及其可能产生的化合物在体内修饰DNA 体外培养。我们将继续阐明主要DNA的结构 α-亚硝胺产生的加合物和其他DNA修饰 醛和3-烷基-1，2，3-恶二唑离子，并测定DNA 由N-亚硝基脱氢吗啉及其环氧化物生成的加合物。3) N-N-的特制氚样品的制备 亚硝酸二乙醇胺、甲基乙醇亚硝胺和N-亚硝基-2- 羟基吗啉与氚同位素效应的测定 这些化合物的酶介导的致突变性，在体内DNA 烷基化，体内和体外DNA单链断裂，顺序为 以揭示哪些生物激活途径是可操作的。4) 通过模拟化学和生物化学实验测定 α-亚硝胺醛和相关醇是否可以被激活 通过连续的一个电子缩短链和/或解毒 包括形成自由基的氧化作用。5) ~(14)C标记N-亚硝二乙醇胺的制备及~(14)C标记 甲基乙醇亚硝胺及其未知DNA的测定 使用上面概述的化学模型作为标记的加合物。结果是 拥有为分子研究提供标记的希望 流行病学和大大提高了我们对化学物质的理解 致癌。

This proposal has as its fundamental and underlying aim a determination of the mechanism by which environmentally prevalent alkyl ethanol nitrosamines, particularly N-nitrosodiethanolamine NDELA, are activated to ultimate carcinogens, and the elucidation of the role that alpha- nitrosamine aldehydes and related compounds may play in this process. Chemical, biochemical, and biological experiments will be used to test the man hypotheses relating to the activation of Beta-nitrosamine ethanols. These hypotheses are: 1) alcohol dehydrogenase mediated oxidation to reactive alpha-nitrosamine aldehydes; 2) Sulfotransferase mediated sulfation followed by the generation of reactive 3-alkyl-1,2,3- oxadiazolinium cations; and 3) chain shortening involving the production of either reactive electrophiles or simple alkyl nitrosamines which are substrates for cytochrome p-450 mediated alpha-hydroxylation. The specific aims are: 1) The determination of the biologically relevant chemistry of alpha-nitrosamine aldehydes, 1,2,3-oxadiazolinium ins, as well as N-nitrosodehydromorpholine and its epoxide in order reveal the likely reactions of these reactive compounds likely to be produced from them modify DNA in vitro. We will continue to elucidate the structure of the major DNA and proteins. 2) The determination of how a-nitrosamine aldehydes and compounds likely to be produced from them modify DNA in vitro. We will continue to elucidate the structure of the major DNA adducts and other DNA modifications produced by alpha-nitrosamine aldehydes, and 3-alkyl-1,2,3-oxadiazolinium ions, and determine the DNA adducts produced from N-nitrosodehydromorpholine and its epoxide. 3) The preparation of specifically deuterated samples of N- nitrosodiethanolamine, methylethanolnitrosamine, and N-nitroso-2- hydroxymorpholine and the determination of the deuterium isotope effects of theses compounds on their enzyme mediated mutagenicity, in vivo DNA alkylation, and in vivo and in vitro DNA single strand breaks, in order to reveal which bioactivation pathways are operative. 4) The determination through model chemical and biochemical experiments of whether a-nitrosamine aldehydes and related alcohols may be activated chain shortened, and/or detoxified through successive one electron oxidations which involve the formation of free radicals. 5) The preparation of 14C-labeled N-nitrosodiethanolamine, and 14C-labeled methylethanolnitrosamine and the determination of their unknown DNA adducts using the chemical models outlined above as markers. The results hold the promise of providing markers for studies in molecular epidemiology and significantly advancing our understanding of chemical carcinogenesis.