THERAPEUTIC ROLE OF ANTIOXIDANTS IN LEAD POISONING

抗氧化剂在铅中毒中的治疗作用

• 批准号: 6224882
• 负责人: NURAN ERCAL
• 金额: $ 11.1万
• 依托单位: MISSOURI UNIVERSITY OF SCIENCE & TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6224882
• 关键词: acetylcysteine; antioxidants; ascorbate; chelating agents; chelation therapy; diet therapy; dietary supplements; drug screening /evaluation; environmental toxicology; laboratory rat; lead poisoning; nonhuman therapy evaluation; nutrition related tag; oxidative stress; pharmacokinetics; short chain fatty acid; taurine; tocopherols; acetylcysteine; antioxidants; ascorbate; chelating agents; chelation therapy; diet therapy; dietary supplements; drug screening /evaluation; environmental toxicology; laboratory rat; lead poisoning; nonhuman therapy evaluation; nutrition related tag; oxidative stress; pharmacokinetics; short chain fatty acid; taurine; tocopherols

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.

尽管在美国每年有300万儿童受到铅中毒的影响，但治疗这些儿童并消除环境中的铅的努力不足。尽管目前可用于治疗铅中毒，但已显示出严重的副作用。 铅中毒被认为是一个多方面的问题，因为 多种生化过程负责毒性，而不是 单个机制。即使氧化压力似乎起着主要作用，但 铅毒性的分子机制并不完全清楚。我们的 先前的研究表明，用硫醇治疗（N-乙酰基脊肉， α-硫酸和卡托普利）显着逆转了铅诱导的 体内和体外的氧化应激参数的改变 型号。但是，这些抗氧化剂均未显示出任何明显的螯合 领导行动。为了提高硫醇的螯合能力 抗氧化剂在治疗铅中毒时，我们建议使用它们 不自然的对映异构体，因为它们的天然，生物活性的对映异构体 迅速代谢，而他们的不自然性却没有。这是由于 生活系统中的酶通常是立体选择性的。所以， 我们的NIH（1R15ES 09497-01）提案的延续将探索螯合 非天然硫醇对映异构体的作用，尤其是D-NAC和D-CySTEINE 在铅中毒中。这项研究将产生更有效和安全的 通过利用生物学依赖性来用于螯合的治疗剂 立体化学。此外，该提案可能会提供有关我们的见解 了解硫醇对映体选择性的机制 一般的。