CARCINOGENESIS--HIGHLY REACTIVE NITROSAMINES

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， 致癌物质通过其醇脱氢酶介导的氧化 反应性α-亚硝胺基-醛。 这些化合物容易 反亚硝酸伯胺和仲胺以及脱氨基 鸟苷。 重氮离子和乙二醛，两种致突变成分， 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。 第二 假设α-亚硝胺醛的水合物可以 是磺基转移酶的底物。 生成的硫酸盐 预期快速产生反应性3-烷基-5-羟基-1，2，3，- 恶二唑啉离子，其在质子损失时可以产生反应性的 也可以由环链产生的恶二唑啉叶立德 母体醛的互变异构。 这些假说和其他关于致癌激活的假说， β-羟基亚硝胺将通过以下方法进行检测：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- 烷基-1，2，3-恶二唑啉鎓离子。 3. 决定阿尔法- 亚硝胺醛和由它们产生的化合物修饰 脱氧寡核苷酸。 4. 通过模型化学和 B-羟基亚硝胺是否被激活的生化研究 通过生成烷氧基，和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。 希望本研究能对建立该机制起到一定的推动作用 B-亚硝胺-乙醇通过其进行致癌活化 以及直接作用的α-亚硝胺醛诱变剂如何修饰DNA。

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.