Role of Selenocystine in Lead Toxicity

硒代胱氨酸在铅毒性中的作用

• 批准号: 6754222
• 负责人: NURAN ERCAL
• 金额: $ 11.18万
• 依托单位: MISSOURI UNIVERSITY OF SCIENCE & TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6754222
• 关键词: PC12 cells; antioxidants; blood chemistry; chelating agents; cystine; drug screening /evaluation; laboratory mouse; lead; lead poisoning; neuroprotectants; neurotoxicology; neurotoxins; oxidative stress; selenated sulfur aminoacid; technology /technique development

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.

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，但治疗这些儿童和从环境中消除铅的努力一直是不够的。虽然目前有一些螯合剂可用于治疗铅中毒，但它们有严重的副作用。铅中毒被认为是一个多方面的问题，因为各种生化过程的中断是造成毒性的原因，而不是单一的机制。尽管氧化应激似乎发挥了主要作用，但铅中毒的分子机制并不完全清楚。我们先前的研究表明，在体内和体外模型中，天然硫醇(N-乙酰半胱氨酸、硫辛酸和牛磺酸)显著逆转了铅诱导的氧化应激参数的变化。然而，这些抗氧化剂都没有表现出对铅的任何明显的螯合作用。在我们寻找潜在的螯合剂和抗氧化剂来治疗铅中毒的过程中，硒半胱氨酸(SeCys)作为一个很好的候选药物得到了我们的关注，因为它的代谢产物是已知的强重金属螯合剂的含有硫醇的化合物。我们的初步结果证明，SeCys不仅是一种有效的抗氧化剂，而且还是一种很好的螯合剂。显著降低血铅水平(50%以上)、组织铅水平(SeCys治疗后脑组织完全无铅)，改善铅诱导的氧化应激，无明显副作用。此外，通过使用神经细胞模型(PC-12细胞)，SeCys显著减弱了铅的神经毒性作用。因此，我们的NIH(2R15 ES 09497-02)建议的继续将主要探讨：1)SeCys的螯合作用，2)SeCys的抗氧化作用，以及3)SeCys在逆转铅中毒的神经毒性效应中的作用。