CARCINOGENESIS--HIGHLY REACTIVE NITROSAMINES

致癌——高活性亚硝胺

• 批准号: 2018317
• 负责人: Richard N Loeppky
• 金额: $ 18.17万
• 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 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2018317
• 关键词: DNA damage; adduct; animal genetic material tag; carcinogen testing; chemical carcinogenesis; cytochrome P450; drug metabolism; enzyme activity; enzyme mechanism; ethanolamines; glutathione; high performance liquid chromatography; isozymes; laboratory rat; liver metabolism; microsomes; mutagen testing; nitrosamines; nuclear magnetic resonance spectroscopy; sulfation

DESCRIPTION: This proposal seeks to understand the mechanism of the carcinogenesis of nitrosodiethanolamine (NDELA) and other beta-oxidized nitrosamines. Secondary alkanolamines are widely distributed and their nitrosoamine derivatives are documented in lubricants and metal-working fluids. NDELA is a known carcinogen but unlike most nitrosodialkylamines, it is not mutagenic in the Ames test in the presence of microsomal enzymes. Thus, beta-oxidized dialkylnitrosamines appear to have a mechanism of activation that is in some way novel. Basically, hypotheses about three modes of activation are entertained with some contribution by each of the three being an additional possibility. a) It is possible that these compounds do undergo the "normal" alpha-oxidation to reactive alpha-hydroxynitrosamines by some as yet unrecognized enzyme activity, but that this was not detected in earlier studies. b) It is possible that these compounds are activated by beta-oxidation to aldehydes that subsequently cyclize and undergo further metabolic activation. c) It is possible that these molecules are activated through sulfation at the beta-position and subsequently form reactive oxadiazolinium ion intermediates. The work proposed involves: synthesis of additional DNA base adducts that could be formed from proposed intermediates; analysis of reaction chemistry and products of model reactions that could account for some known adducts and or reactions; establishing whether NDELA is in fact a substrate for some microsomal enzymes, analysis of isotope effects on 32P-postlabeling profiles to determine the dependence of adducts upon the site of oxidation; and analysis of formation in vivo of an adduct isolated from in vitro reactions that is characteristic of one of the pathways above.

描述：本提案旨在了解该机制的机制 亚硝基二乙醇胺 (NDELA) 和其他 β-氧化化合物的致癌作用 亚硝胺。 仲烷醇胺分布广泛，其 亚硝胺衍生物被记录在润滑剂和金属加工中 液体。 NDELA 是一种已知的致癌物质，但与大多数亚硝基二烷基胺不同， 在微粒体酶存在的情况下，在艾姆斯试验中它不具有致突变性。 因此，β-氧化二烷基亚硝胺似乎具有以下机制： 激活在某种程度上是新颖的。 基本上，关于三个假设 激活模式受到每个人的一些贡献的欢迎 三是另一种可能性。 a) 这些可能是 化合物确实经历了“正常”的α-氧化反应 α-羟基亚硝胺是通过一些尚未被识别的酶活性产生的，但是 这在早期的研究中没有被发现。 b) 这些可能是 化合物通过β-氧化成醛而被激活，随后 环化并进行进一步的代谢激活。 c) 有可能 这些分子通过 β 位硫酸化被激活 随后形成反应性恶二唑啉鎓离子中间体。 工作 提议涉及： 合成额外的 DNA 碱基加合物 由提议的中间体形成；反应化学分析和 模型反应的产物可以解释一些已知的加合物和/或 反应；确定 NDELA 是否确实是某些物质的底物 微粒体酶，同位素对 32P 标记后谱的影响分析 确定加合物对氧化位点的依赖性；和 分析从体外反应中分离出的加合物的体内形成 这是上述途径之一的特征。