CARCINOGENESIS: HIGHLY REACTIVE NITROSAMINES

致癌：高反应性亚硝胺

• 批准号: 3251720
• 负责人: Richard N Loeppky
• 金额: $ 14.48万
• 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/3251720
• 关键词: alcohol dehydrogenase; aldehydes; chemical carcinogen; chemical carcinogenesis; chemical structure function; chemical substitution; 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-亚硝基氨基乙醇被激活 通过乙醇脱氢酶介导的氧化作用致癌 反应性α-亚硝基氨基醛。 这些化合物很容易 转亚硝基伯胺和仲胺以及脱氨 鸟苷。 重氮离子和乙二醛都是诱变成分， 也由它们产生，但它们与鸟苷的反应 产生许多有待确定的产品。 一秒钟 假设是 α-亚硝基氨基醛的水合物可能 是磺基转移酶的底物。 生成的硫酸盐 预计会快速产生反应性3-烷基-5-羟基-1,2,3,- 恶二唑啉鎓离子，在质子丢失时可以产生反应性 也可以由环链产生的恶二啉叶立德 母体醛的互变异构。 这些假设和其他关于致癌激活的假设 β-羟基亚硝胺将通过以下方式进行测试： 1. 确定 转亚硝化反应的机理。 2. 检查 亲核试剂、弱碱和核苷与 3- 的反应 烷基-1,2,3-恶二唑啉鎓离子。 3. 确定α- 亚硝胺醛和由它们产生的化合物可以修饰 脱氧寡核苷酸。 4.通过模型化学和确定 生化研究 B-羟基亚硝胺是否被激活 通过烷氧基自由基的产生，以及5.确定 特定酶抑制剂对转化的影响 β-羟基亚硝胺和α-亚硝胺醛。 这项研究有望在机制建立方面取得更大进展 B-亚硝胺-乙醇通过其发生致癌激活 以及a-亚硝基氨基-醛诱变剂如何直接作用修改DNA。