HYDROPEROXIDE DERIVED FREE RADICALS

工作总结：衍生活性中间体的不利影响 来自有毒化学物质，主要是由于共价结合到 大分子和脂质过氧化。因为它的核心作用 脂质过氧化在毒性机制中的研究进展 这一过程已经完成。脂肪酸氢过氧化物不是形成的 不仅在自由基介导的毒性方面，而且在生理上也是如此。 多不饱和脂肪酸(PUFA)过氧化产物 前列腺素H合成酶和脂氧合酶。 多不饱和脂肪酸衍生的过氧化氢与血红素和各种血红蛋白一起存在。 尽管多不饱和脂肪酸衍生的自由基的形成是由 Tappl于1953年提出，随后用ESR检测到自由基， 它们与血红素蛋白的反应机理(S)一直是 有相当多的争论。提出了不同的反应机理 含有过氧化氢的血红素蛋白表明初始自由基 产生的是过氧基(如杂裂基预测的那样 过氧化物酶机制)，烷氧基自由基(通过均一分解机制)， 或过氧基和烷氧基两者(通过Haber-Weiss类型 机制)。最初的自由基的反应发生在 它的产生可以通过增加其浓度来抑制 用于检测和鉴定这些活性物质的自旋陷阱 物种。因此，随着添加更多的自旋陷阱，更多的初始自由基 被困住了。这防止了最初的自由基与 导致次生自由基的其他物种或其本身。通过这样做， 一个人可以确定哪一个部首是 多组分ESR波谱。我们使用这一策略来确定 过氧基或烷氧基是由 血红素蛋白与过氧化氢的反应。在所审查的每一宗个案中 到目前为止(即细胞色素C、血红素和细胞色素P-450)的烷氧基 在DMPO浓度最高时，自由基加合物完全占优势。 因此，ESR数据为同源断裂提供了强有力的证据。 最初产生烷氧基的血红蛋白的过氧化氢O-O键 激进分子。

Summary of Work: The adverse effects of reactive intermediates derived from toxic chemicals result primarily from covalent binding to macromolecules and lipid peroxidation. Because of the central role of lipid peroxidation in the mechanisms of toxicity, many investigations of this process have been made. Fatty acid hydroperoxides are formed not only in free radical-mediated toxicities, but also physiologically as products of the peroxidation of polyunsaturated fatty acids (PUFA) by prostaglandin H synthases and lipoxygenases.One of the major reactions of PUFA-derived hydroperoxides is with hematin and various hemoproteins. Although the formation of PUFA-derived free radicals was proposed by Tappel in 1953 and free radicals were subsequently detected with ESR, the mechanism(s) of their reaction with hemoproteins has been the subject of considerable debate. The different mechanisms proposed for the reaction of hemoproteins with hydroperoxides dictate that the initial radical produced is either the peroxyl radical (as predicted by the heterolytic peroxidase mechanism), the alkoxyl radical (via the homolytic mechanism), or both the peroxyl and alkoxyl radicals (via the Haber-Weiss-type mechanism). The reactions of the initial radical that occur subsequent to its production can be suppressed by increasing the concentration of the spin trap used in the detection and identification of these reactive species. Thus, as more spin trap is added, more of the initial radical is trapped. This prevents the initial radical from undergoing reactions with other species or itself that lead to secondary radicals. By doing this, one can determine which radical is the primary or initial radical in a multiple species ESR spectrum. We used this strategy to determine whether the peroxyl or the alkoxyl radical was the initial radical produced by the reaction of hemoproteins with hydroperoxides. In every case examined thus far (i.e., cytochrome c, hematin, and cytochrome P-450) the alkoxyl radical adduct completely dominated at the highest DMPO concentrations. Thus, the ESR data provides strong evidence for the homolytic scission of the hydroperoxide O-O bond by hemoproteins initially producing alkoxyl radicals.