Role of Selenocystine in Lead Toxicity

描述（申请人提供）：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还不够。虽然螯合剂目前可用于治疗铅中毒，但它们具有严重的副作用。铅中毒被认为是一个多方面的问题，因为破坏各种生化过程是负责毒性，而不是一个单一的机制。尽管氧化应激似乎起着重要作用，但铅毒性的分子机制尚不完全清楚。我们以前的研究表明，治疗与天然硫醇（N-乙酰半胱氨酸，硫辛酸和牛磺酸）显着逆转铅诱导的氧化应激参数的改变，在体内和体外模型。然而，这些抗氧化剂都没有表现出任何显着的螯合作用的铅。在我们寻找潜在的螯合剂和抗氧化剂治疗铅中毒，硒代胱氨酸（SeCys）获得了我们的注意，作为一个很好的候选人，因为它的代谢产物是含巯基的化合物，已知是强的重金属螯合剂。我们的初步结果证明，SeCys不仅是一种有效的抗氧化剂，但它也是一个很好的螯合剂。它显著降低了血铅水平（超过50%），组织铅水平（SeCYs治疗后脑组织完全无铅），并改善了铅诱导的氧化应激，没有明显的副作用。此外，通过使用神经元细胞模型（PC-12细胞），SeCys显着减少铅的神经毒性作用。因此，我们的NIH（2 R15 ES 09497-02）提案的延续将主要探索：1）SeCys的螯合作用，2）SeCys的抗氧化作用，以及3）SeCys在逆转铅中毒中铅的神经毒性作用中的作用。

DESCRIPTION (provided by applicant): 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 severe side effects. Lead poisoning is considered 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 natural thiols (N-acetylcysteine, lipoic acid and taurine) significantly reversed lead-induced alterations in oxidative stress parameters, both in in vivo and in vitro models. However, none of these antioxidants showed any significant chelating action for lead. In our search for potential chelators and antioxidants for the treatment of lead poisoning, selenocystine (SeCys) gained our attention as a good candidate because its metabolic products are thiol-containing compounds known to be strong heavy metal chelators. Our preliminary results proved that SeCys is not only an effective antioxidant but it is also a good chelator. It significantly reduced blood lead levels (more than 50%), tissue lead levels (brain tissue was completely lead free after SeCYs treatment) and improved lead-induced oxidative stress, with no obvious side effects. Moreover, neurotoxic effects of lead were significantly diminished by SeCys by using a neuronal cell model (PC-12 cells). Therefore, this continuation of our NIH (2R15ES 09497-02) proposal will primarily explore: 1) chelating action of SeCys, 2) antioxidant role of SeCys, and 3) role of SeCys in reversing the neurotoxic effects of lead in lead poisoning.