Strategies for Heavy Metal Detoxification

重金属排毒策略

• 批准号: 8462622
• 负责人: GERARD PARKIN
• 金额: $ 24.65万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462622
• 关键词: Acute; Affinity; Bacteria; Binding; Biochemical; Biochemistry; Bread; Cadmium; Carbon; Cause of Death; Cessation of life; Chelating Agents; Chelation Therapy; Chemicals; Chemistry; Child; Chromium; Chronic; Cleaved cell; Copper; Cysteine; Data; Disease; Disease Outbreaks; Drug Metabolic Detoxication; Effectiveness; Elements; Environment; Enzymes; Excretory function; Factor Analysis; Fishes; Gasoline; Goals; Health; Heavy Metals; Human; Investigation; Ions; Iraq; Japan; Lead; Lead Poisoning; Life; Ligands; Mercury; Mercury Poisoning; Metals; Methods; Methylmercury Compounds; Mission; Molecular; Nature; Paint; Pesticides; Plants; Plumbing; Poisoning; Process; Property; Proteins; Protons; Public Health; Rattus; Research; Risk; Role; Seeds; Selenium; Structure; Sulfur; Techniques; Thermodynamics; Toxic effect; United States; United States National Institutes of Health; Wheat; Zinc; analog; biological systems; combat; design; divalent metal; improved; in vivo; innovation; insight; metal poisoning; public health relevance; small molecule; toxic metal

DESCRIPTION (provided by applicant): Mercury and lead are pervasive in the environment and pose a severe risk to human health worldwide. The purpose of the proposed research is to develop new and innovative detoxification strategies for these metals. Organomercury compounds, in particular, are highly toxic as illustrated by the death of almost two thousand people around Minamata Bay (Japan) in the late 1950s when the residents consumed fish that were contaminated with methyl mercury compounds. Furthermore, the use of organomercurials as pesticides resulted in the death of ca 500 people in Iraq in the early 1970s when wheat seeds treated with these pesticides were used for making bread rather than for growing wheat. While the outbreak of methyl mercury poisoning in Japan was a result of toxic release from a nearby chemical plant, methyl mercury compounds are also introduced into the environment by biomethylation of naturally occurring Hg(II) in an aquatic environment and accumulate in predatory fish. Likewise, the occurrence of lead in the environment is a consequence of its current and previous widespread use in, for example, batteries, gasoline, plumbing and paints, such that lead poisoning is the most common environmentally induced disease among children in the United Stated today. It is, therefore, evident that the discovery of improved detoxification strategies for metals such as mercury and lead would be of considerable benefit for human health. A central component of the proposed research will be to elucidate the biological chemistry of these metals that will facilitate detoxification. This objective will be achieved by using a synthetic analogue approach in which small molecules are used to mimic the biological system. Since the toxic effects of mercury and lead are largely a consequence of the ability of these metals to bind effectively to the cysteine residues of proteins, specific emphasis will be given to the application of ligands that feature sulfur donors. The protolytic cleavage of the Hg-C bond is an important component of mercury detoxification in bacteria and so considerable effort will be directed towards understanding the factors that influence this process, so that improved detoxification strategies can be developed for human applications. In this regard, the primary treatment of heavy metal poisoning is chelation therapy, but the effectiveness of this technique is far from ideal. Therefore, new strategies for chelation therapy will be developed by directing effort towards discovering molecules that chelate toxic metals more effectively. For example, multidentate ligands that feature arenethiol groups will be investigated since these groups may serve the dual purpose of both cleaving a Hg-C bond and coordinating the mercury. Furthermore, effort will be directed towards discovering compounds that promote Hg-C bond cleavage in vivo, and which may be used in conjunction with traditional chelating agents. Both of these approaches are important because they represent significant advances over the methods currently employed.

描述（由申请人提供）：汞和铅在环境中普遍存在，对全球人类健康构成严重风险。拟议研究的目的是为这些金属开发新的创新解毒策略。有机汞化合物尤其具有剧毒性，20世纪50年代末，水俣湾（日本）附近有近2000人因食用受甲基汞化合物污染的鱼类而死亡。此外，在1970年代初，使用有机汞农药作为杀虫剂导致伊拉克约500人死亡，当时用这些杀虫剂处理过的小麦种子被用于制作面包，而不是种植小麦。虽然日本爆发的甲基汞中毒是附近一家化工厂释放有毒物质的结果，但甲基汞化合物也通过水生环境中天然存在的Hg（II）的生物甲基化作用进入环境，并在食肉鱼类体内积累。同样，铅在环境中的出现是其当前和以前广泛使用的结果，例如电池、汽油、管道和油漆，因此铅中毒是当今美国儿童中最常见的环境诱发疾病。因此，很明显，发现汞和铅等金属的改进解毒战略将对人类健康产生巨大的益处。拟议研究的一个核心组成部分将是阐明这些金属的生物化学，这将有助于解毒。这一目标将通过使用合成类似物方法来实现，其中小分子用于模拟生物系统。由于汞和铅的毒性作用很大程度上是这些金属有效结合蛋白质半胱氨酸残基的能力的结果，因此将特别强调以硫供体为特征的配体的应用。Hg-C键的质子裂解是细菌中汞解毒的一个重要组成部分，因此将做出相当大的努力来了解影响这一过程的因素，以便为人类应用开发更好的解毒策略。在这方面，重金属中毒的主要治疗方法是螯合疗法，但这种技术的效果远不理想。因此，螯合治疗的新策略将通过将努力导向发现更有效地螯合有毒金属的分子来开发。例如，将研究具有芳硫醇基团的多齿配体，因为这些基团可以用于裂解Hg-C键和配位汞的双重目的。此外，努力将致力于发现促进体内Hg-C键裂解的化合物，并且其可以与传统螯合剂结合使用。这两种方法都很重要，因为它们代表了目前采用的方法的重大进步。