QUINONE METHIDE TOXICITY

醌甲基化物毒性

• 批准号: 2154847
• 负责人: DAVID C THOMPSON
• 金额: $ 9.27万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-06-01 至 1997-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2154847
• 关键词: adduct; butylated hydroxytoluene; chemical addition; chemical reaction; chemical synthesis; cytochrome P450; cytotoxicity; enzyme activity; hepatotoxin; high performance liquid chromatography; laboratory mouse; laboratory rat; mass spectrometry; nuclear magnetic resonance spectroscopy; peroxidases; phenols; quinones; respiratory toxin; thin layer chromatography; tissue /cell culture; toxicant interaction; toxin metabolism

Most xenobiotics must be metabolized to exert their toxic or carcinogenic effects. Pan research has focused on the formation of reactive electrophilic intermediates as mediators of these deleterious processes. Two widely studied classes of reactive intermediates are quinones and quinoneimines. A structurally related class of chemical intermediates, quinone methides, has received surprisingly little attention. Phenolic compounds with ortho or para alkyl groups are capable of forming quinone methides. This includes a large number of chemicals present in foods and medicines. It is our hypothesis that the toxicity of certain phenolic compounds can be explained, in part, by their metabolism to reactive quinone methides, which in turn covalently bind to cellular macromolecules. Previous work has demonstrated that quinone methides are formed during xenobiotic metabolism of a limited number of phenolic compounds, but data showing a causal linkage between quinone methide formation and toxicity is lacking. Butylated hydroxytoluene and eugenol are examples of phenolic compounds for which the formation of reactive quinone methide intermediates has been suggested to play a role in the hepatic and pulmonary toxicity of these compounds. This proposal seeks to measure and quantify the amount of quinone methides formed during the oxidative metabolism of butylated hydroxytoluene, eugenol and related phenols and to link the formation of these reactive intermediates to toxicity. seen in isolated liver cells or tissue slices from liver or lung. Analogs of these compounds which cannot form quinone methide metabolites will be used to assess the role of other possible mechanisms of toxicity. In addition, stable quinone methides from these compounds will be tested directly on cells and tissue slices for their possible cytotoxic effects and mechanism of toxicity.

大多数外来物质必须经过代谢才能发挥其毒性或致癌作用。 效果。PAN研究的重点是反应性的形成 亲电中间体作为这些有害过程的中介体。 两类被广泛研究的活性中间体是苯二酮和 喹诺亚胺。一类结构上相关的化学中间体， 令人惊讶的是，这种药物很少受到人们的关注。酚类 具有邻位或对位烷基的化合物能够形成苯二酚 甲基米德。这包括食品中存在的大量化学物质和 药物。我们的假设是某些酚类化合物的毒性 化合物可以部分地用它们的新陈代谢来解释。 甲基苯二酚，进而共价结合到细胞大分子上。 以前的工作已经证明，甲基苯醌在 有限数量的酚类化合物的异种生物代谢，但数据 表明在苯二酚的形成和毒性之间存在因果联系 缺乏。丁基羟基甲苯和丁香酚是酚类的例子。 具有反应性的苯醌甲醚中间体形成的化合物 已被认为在肝和肺毒性中发挥作用 这些化合物。这项建议旨在衡量和量化 丁基化产物氧化代谢过程中生成的甲基苯醌 羟基甲苯、丁香酚和相关酚类的形成与联系 这些活性中间体会产生毒性。在分离的肝细胞或 取自肝脏或肺的组织切片。这些化合物的类似物，不能 形式的醌甲基代谢物将被用来评估其他 可能的毒性机制。此外，稳定的苯二酚甲基从 这些化合物将直接在细胞和组织切片上进行测试 其可能的细胞毒作用及其毒性机制。