BIOCHEMISTRY AND HEPATIC TOXICITY OF CARBON RADICALS

碳自由基的生物化学研究相对较少。 关注，尽管碳和碳的生物联系密切 氧自由基与当前人们对氧自由基的强烈兴趣 病理学。这项提案对碳自由基的关注反映了， 此外，它们作为机械探头的独特价值。这个 拟议的工作是在过去一段时间取得的主要进展的基础上进行的 支持，特别是(A)制定支持的理由 自由基是由过氧化物酶产生的，而不是 单加氧酶，(B)蛋白质自由基支持的发现 共氧化反应，以及(C)改进自旋的发展 诱捕技术。第一个目标是阐明 过氧化物酶的作用机制以及确定其有效性 关于反应产生可扩散自由基的建议 使用血红素边缘而不是活性氧气。第二 目标是进一步探索底物之间的关系 可扩散碳自由基的结构和产生 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，特别是它们被氧化成 阳离子及其与不饱和目标的反应。决赛 目标是阐明涉及到的迁移的机制 自由基中心从一个蛋白质残基转移到另一个蛋白质残基及其作用 蛋白质与药物和DNA的氧化结合中的酪氨酸。 这些研究的集体意图是推动我们的 对碳自由基生物化学的理解 阐明它们的毒理潜力。

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.