CARCINOGENESIS--HIGHLY REACTIVE NITROSAMINES

致癌——高活性亚硝胺

• 批准号: 3251717
• 负责人: Richard N Loeppky
• 金额: $ 12.85万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-12-06 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251717
• 关键词: alcohol dehydrogenase; aldehydes; chemical carcinogen; chemical carcinogenesis; chemical structure function; diazo compound; environment related neoplasm /cancer; ethanol; glyoxal; mutagens; nitrosamines; oligonucleotides; sulfotransferase

The principal hypothesis of the proposed research is that environmentally prevalent B-nitrosaminos-ethanols are activated to carcinogens through their alcohol dehydrogenase mediated oxidation to reactive a-nitrosamino-aldehydes. These compounds readily transnitrosate primary and secondary amines and deaminate guanosine. Diazonium ions and glyoxal, both mutagenic components, are also produced from them, but their reaction with guanosine generates many products which remain to be determined. A second hypothesis is that hydrates of the alpha-nitrosamino-aldehydes may be substrates for sulfotransferase enzymes. The resulting sulfates are expected to rapidly produce reactive 3-alkyl-5-hydroxy-1,2,3,- oxadiazolinium ions, which upon proton loss could generate reactive oxadiaoline ylides which could also be produced from the ring-chain tautomerism of the parent aldehydes. These hypotheses and others for the carcinogenic activation of beta-hydroxynitrosamines will be tested by: 1. Determining the mechanism of the transnitrosation reaction. 2. Examining the reactions of nucleophiles, mild bases, and nucleosides with 3- alkyl-1, 2, 3-oxadiazolinium ions. 3. Determining how alpha- nitrosamino-aldehydes and compounds produced from them modify deoxy-oligonucleotides. 4. Determining through model chemical and biochemical studies whether B-hydroxynitrosamines are activated through the generation of alkoxy radicals, and 5. Determining the effects of specific enzyme inhibitors on the transformations of beta-hydroxynitrosamines and alpha-nitrosamino-aldehydes. This research is expect to go far toward establishing the mechanism by which B-nitrosamino-ethanols undergo carcinogenic activation and how direct action a-nitrosamino -aldehyde mutagens modify DNA.

拟议研究的主要假设是 环境中普遍存在的B-亚硝胺-乙醇被活化以 致癌物通过其酒精脱氢酶介导的氧化 使α-亚硝胺-醛发生反应。这些化合物很容易 反式亚硝酸盐、伯胺、仲胺和脱胺 鸟苷。重氮离子和乙二醛，都是诱变成分， 也是由它们产生的，但它们与鸟苷的反应 产生了许多有待确定的产品。一秒钟 假设α-亚硝胺-醛的水合物可能 硫基转移酶的底物。由此产生的硫酸盐 有望迅速产生活性3-烷基-5-羟基-1，2，3，- 恶二唑离子，在质子损失时可能产生反应性 也可以从环链中生成的恶二唑啉叶立德 母醛的互变异构化。 这些假说和其他关于致癌活性的假说 测试β-羟基亚硝胺的方法如下：1.测定 反硝化反应的机理。2.检视 亲核试剂、温和的碱和核苷与3-羟基-3-羟基-4-羟基-4-羟基-4-羟基-4-羟基-4-羟基的反应 烷基-1，2，3-恶二唑离子。3.确定阿尔法如何- 亚硝胺醛及其生成的化合物改性 脱氧寡核苷酸。4.通过模型化学和化学方法测定 生化研究B-羟基亚硝胺是否被激活 通过生成烷氧基，以及5.测定 特异酶抑制剂对乳酸菌转化的影响 β-羟基亚硝胺和α-亚硝胺-醛。 这项研究有望为建立这一机制做出更大的贡献 B-亚硝胺-乙醇的致癌活性 以及直接作用的α-亚硝胺醛致突变剂如何改变DNA。