THERAPEUTIC ROLE OF ANTIOXIDANTS IN LEAD POISONING

尽管美国每年有300万儿童受到铅中毒的影响，但治疗这些儿童和消除环境中铅的努力一直不够。虽然螯合剂目前可用于治疗铅中毒，但它们已被证明具有严重的副作用。 铅中毒被认为是一个多方面的问题， 各种生化过程是负责毒性，而不是一个 单一机制尽管氧化应激似乎起着重要作用， 铅毒性的分子机制尚不完全清楚。我们 先前的研究表明用硫醇（N-乙酰半胱氨酸， α-硫辛酸和巯甲丙脯酸）显著逆转铅诱导的 体内和体外氧化应激参数的改变 模型然而，这些抗氧化剂都没有显示出任何显著的螯合作用， 铅的行动。为了提高巯基的螯合能力， 抗氧化剂治疗铅中毒，我们建议使用 非天然的对映体，因为它们的天然的、生物活性的对映体 被迅速代谢而非天然的则不然这是由于 生命系统中的酶通常具有立体选择性。因此，我们认为， 我们NIH（1 R15 ES 09497-01）提案的延续将探索螯合 非天然硫醇对映体，特别是D-NAC和D-半胱氨酸的作用 铅中毒这项研究将产生更有效和安全的 利用生物依赖性的螯合治疗剂 立体化学此外，该提案可能会对我们的 了解硫醇的对映体选择性的机制， 将军

Despite the fact that 3 million children are affected by lead poisoning each year in the United States, efforts to treat these children and to eliminate lead from the environment have been inadequate. Although chelating agents are currently available for the treatment of lead poisoning, they have been shown to have severe side effects. Lead poisoning is stated as a multifaceted problem since disruption of a variety of biochemical processes is responsible for toxicity rather than a single mechanism. Even though oxidative stress appears to play a major role, the molecular mechanisms of lead toxicity are not completely known. Our previous studies demonstrated that treatment with thiols (N-acetylcystein, alpha-lipoic acid and captopril) significantly reversed lead-induced alterations in oxidative stress parameters, in both in vivo and in vitro models. However, none of these antioxidants showed any significant chelating action for lead. In order to improve the chelating abilities of thiol antioxidants in the treatment of lead poisoning, we propose to use their unnatural enantiomers because their natural, biologically-active enantiomers are quickly metabolized, whereas their unnatural ones are not. This is due to the fact that enzymes in living systems are usually stereoselective. Therefore, this continuation of our NIH (1R15ES 09497-01) proposal will explore chelating actions of the unnatural thiol enantiomers, particularly D-NAC and D-Cysteine in lead poisoning. This research will produce more effective and safe therapeutic agents for chelation by exploiting biological dependence on stereochemistry. In addition, the proposal may offer insights into our understanding of the mechanisms of enantiomeric selectivity of thiols in general.