ENDOGENOUS NITROSATION CHEMISTRY IN CARCINOGENESIS

致癌过程中的内源亚硝化化学

• 批准号: 6377782
• 负责人: Richard N Loeppky
• 金额: $ 19.58万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377782
• 关键词: adduct; aldehydes; amidines; aminoacid; benzodiazepines; chemical carcinogen; chemical carcinogenesis; cyanides; dietary constituent; food; ketones; mutagens; nitric oxide; nitrosamines; nitroso compounds; nutrition related neoplasm /cancer; nutrition related tag

The goal of this research is to provide knowledge and practical strategies for the significant reduction of carcinogenesis which may arise from endogenous nitrosation processes which can generate electrophilic species capable of modifying DNA and causing mutations. The principle hypothesis of this proposal is that significant progress toward this goal can be achieved 1) by showing through logical experimentation what can be made; 2) by elucidating the chemistry of processes which may catalyze or otherwise facilitate, as well as block, the N-nitrosation of available substrates and the production of electrophiles, and 3) by providing available markers, such as DNA adducts or other products, of genotoxicity which could be used in epidemiological studies to make connections between endogenous nitrosation chemistry and cancer. Our focus is directed at revealing the role that nitrosation of compounds containing C-N double bonds may play in the generation of cell damaging electrophiles, and how this process, as well as the nitrosation of other substrates, may occur through the reaction of NO with radical cations produced by oxidation processes such as those which occur at inflammation sites. Model substrates and drugs containing the oxazoline, imidazoline, and benzodiazepine rings will be nitrosated under endogenous conditions and the nature of the electrophiles arising from these transformations identified and the nature of their DNA adducts determined when appropriate. Both acidic nitrosation and NO + O2 Dietary aldehydes and ketones, including sugars, will be examined for their ability to catalyze the nitrosative conversion of primary amines, including amino acids, to diazonium ions, alpha-acyloxynitrosamines, or alpha-hydroxynitrosamines. The ability of NO mediated damage to occur by its reaction with radical cations produced by other oxidative processes will be probed. Computational methods will be employed to reveal reaction paths of intermediates and lead to better predictions of the types of compounds which pose a carcinogenic threat through their endogenous nitrosation.

本研究的目的是提供知识和实用策略，以显着减少因内源亚硝化过程而产生的致癌作用，该过程可产生能够修饰 DNA 并引起突变的亲电子物质。 该提案的主要假设是，可以通过以下方式实现这一目标的重大进展：1）通过逻辑实验展示可以做什么； 2) 通过阐明可能催化或以其他方式促进以及阻止可用底物的 N-亚硝化和亲电子试剂产生的化学过程，以及 3) 通过提供遗传毒性的可用标记，例如 DNA 加合物或其他产物，可用于流行病学研究，以建立内源亚硝化化学与癌症之间的联系。我们的重点是揭示含有 C-N 双键的化合物的亚硝化在细胞损伤性亲电子试剂的产生中可能发挥的作用，以及该过程以及其他底物的亚硝化如何通过 NO 与氧化过程（例如发生在炎症部位的氧化过程）产生的自由基阳离子的反应而发生。含有恶唑啉、咪唑啉和苯并二氮杂环的模型底物和药物将在内源条件下被亚硝化，并在适当时确定由这些转化产生的亲电子试剂的性质以及它们的DNA加合物的性质。酸性亚硝化和 NO + O2 膳食醛和酮（包括糖）将检查其催化伯胺（包括氨基酸）亚硝化转化为重氮离子、α-酰氧基亚硝胺或 α-羟基亚硝胺的能力。将探讨 NO 介导的损伤通过与其他氧化过程产生的自由基阳离子反应而发生的能力。将采用计算方法来揭示中间体的反应路径，并更好地预测通过内源亚硝化构成致癌威胁的化合物类型。