TOXICITY OF CATECHOL THIOETHER ADDUCTS

特发性帕金森病(PD)是一种衰弱的，进行性的， 神经退行性疾病。流行病学研究已经确定了年龄 暴露于金属和其他毒物是帕金森病的危险因素。 氧化应激和线粒体功能障碍被认为是 帕金森病神经元死亡的基本原因。这项研究的目的是 建议定义儿茶酚加成在糖尿病的发生中的作用 警察。儿茶酚可以通过过渡金属催化的自氧化反应来 然后在一种称为儿茶酚的过程中再次还原为儿茶酚 氧化还原自行车。儿茶酚到对苯二酚的氧化还原循环导致 细胞毒性活性氧的产生及其与细胞毒性的关系 邻苯二酚硫醚通过在苯二酚上加成硫醇而形成加合物。 邻苯二酚硫醚加合物具有较低的氧化电位，并且可以 氧化还原循环的速度比母儿茶酚快。前两个 这项研究的具体目的是测试儿茶酚 硫醚加合物可以产生更多的活性氧物种和加合物 蛋白质比天然儿茶酚的速率更快。这将是 通过测量邻苯二酚硫醚的氧化电位来实现 加合物，由这些加合物产生的活性氧物种，以及 这些加合物对蛋白质的加合速率。的最后一个具体目标 这项建议是为了测试邻苯二酚加成对 线粒体功能。这将通过研究 儿茶酚加合物对线粒体呼吸的影响 呼吸复合体和线粒体电子载体。

Idiopathic Parkinson's disease (PD) is a debilitating, progressive, neurodegenerative disease. Epidemiological studies have identified age and exposure to metals and other toxicants as risk factors for PD. Oxidative stress and mitochondrial dysfunction are hypothesized to be the basic causes of neuron death in PD. The objective of this research proposal is to define the role of catechol adduction in the genesis of PD. Catechols can undergo transition metal-catalyzed autoxidation to quinones and then be reduced to catechols again in a process termed redox cycling. The redox cycling of catechols to quinones leads to the generation of cytotoxic reactive oxygen species and to the formation of catechol thioether adducts via the addition of a thiol to the quinone. A catechol thioether adduct has a lower oxidation potential and may redox cycle at a faster rate than the parent catechol. The first two specific aims of this research are designed to test whether catechol thioether adducts can generate more reactive oxygen species and adduct proteins at a greater rate than native catechols. This will be accomplished by measuring the oxidation potentials of catechol thioether adducts, the reactive oxygen species generated by these adducts, and the rate of protein adduction by these adducts. The last specific aim of this proposal is to test the effects of catechol adduction upon mitochondrial function. This will be accomplished by studying the effects of catechol adducts upon mitochondrial respiration, specific respiratory complexes, and mitochondrial electron carriers.