BIOCHEMISTRY AND HEPATIC TOXICITY OF CARBON RADICALS

碳自由基的生物化学和肝毒性

• 批准号: 3281377
• 负责人: Paul R Ortiz De Montellano
• 金额: $ 17.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3281377
• 关键词: carbazoles; carbon; chemical structure function; cytochrome P450; drug metabolism; electron spin resonance spectroscopy; electronic spectra; enzyme inhibitors; enzyme mechanism; free radicals; gas chromatography; hepatotoxin; high performance liquid chromatography; hydrazines; indoles; laboratory rat; mass spectrometry; nuclear magnetic resonance spectroscopy; oxidation reduction reaction; peroxidases; toxicant interaction; toxin metabolism; ultraviolet spectrometry

The biochemistry of carbon radicals has received relatively little attention despite the close biological association of carbon and oxygen radicals and the intense current interest in oxygen radical pathology. The focus of this proposal on carbon radicals reflects, in addition, their unique value as mechanistic probes. The proposed work builds on key advances made during the past period of support, particularly (a) the formulation of a rationale for the fact that radicals are produced by peroxidases but not monooxygenases, (b) the finding that protein radicals support cooxidation reactions, and (c) the development of improved spin trapping technology. The first goal is to elucidate the mechanisms of peroxidases and to determine the validity of the proposal that diffusible radical generation results from reaction with the heme edge rather than the activated oxygen. The second goal is to explore further the relationship between substrate structure and the production of diffusible carbon radicals by cytochrome P-450. The third goal is to continue the development of new spin traps and their use in studies of the physiological incidence of carbon radicals. The fourth goal is to explore the biological fates of carbon radicals, particularly their oxidation to cations and their reactions with unsaturated targets. The final goal is to elucidate the mechanisms involved in the migration of a radical center from one protein residue to another and the role of tyrosines in the oxidative binding of proteins to drugs and DNA. The collective intent of these studies is to advance our understanding of the biochemistry of carbon radicals and to clarify their toxicological potential.

碳自由基的生物化学受到的关注相对较少 尽管碳和碳的生物学联系密切， 氧自由基和对氧自由基的强流兴趣 病理 这项提案对碳自由基的关注反映了， 此外，它们作为机械探针的独特价值。 的 拟议工作借鉴了上一期间取得的主要进展 特别是（a）拟订一项理由， 自由基是由过氧化物酶产生的， 单加氧酶，（B）蛋白质自由基支持的发现 共氧化反应，和（c）改进的自旋的发展 诱捕技术 第一个目标是阐明 过氧化物酶的机制，并确定的有效性， 扩散自由基产生是反应的结果 而不是活性氧 第二 目的是进一步探索基质与 结构和可扩散碳自由基的产生， 细胞色素P-450 第三个目标是继续发展 新的自旋陷阱及其在生理学研究中的应用 碳自由基的发生率。 第四个目标是探索 碳自由基的生物命运，特别是它们的氧化， 阳离子及其与不饱和目标的反应。 最终 目的是阐明参与迁移的机制， 自由基中心从一个蛋白质残基到另一个， 酪氨酸在蛋白质与药物和DNA的氧化结合中的作用。 这些研究的共同目的是促进我们的 了解碳自由基的生物化学， 阐明其毒理学潜力。