Strategies for Heavy Metal Detoxification

重金属排毒策略

• 批准号: 8255499
• 负责人: GERARD PARKIN
• 金额: $ 25.61万
• 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/8255499
• 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. PUBLIC HEALTH RELEVANCE: Mercury and lead are the two most toxic metals that are commonly encountered in the environment and are a severe risk to human health worldwide; as such, the discovery of improved detoxification strategies for these metals is of considerable importance to public health issues. A specific objective of the proposed research is to elucidate the chemistry of toxic metals in biological systems in order to enable the discovery of desperately needed new detoxification strategies. The proposed research is, therefore, relevant to the NIH mission of developing fundamental information that serves to reduce the burden of human illness.

描述（由申请人提供）：汞和铅在环境中普遍存在，并对全球人类健康构成严重风险。拟议的研究的目的是为这些金属制定新的创新排毒策略。 1950年代后期，当居民食用被甲基汞化合物污染的鱼类时，尤其是有机汞化合物剧毒剧毒。此外，在1970年代初期，使用有机核作为农药的使用导致伊拉克500人死亡，当时用这些农药处理的小麦种子用于制作面包，而不是生长小麦。虽然日本甲基汞中毒的爆发是由于附近的化学植物有毒释放的结果，但还通过在水生环境中自然存在的汞（II）生物甲基化并在捕食性鱼类中积聚，从而引入了甲基汞化合物。同样，环境中铅的发生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，因此铅中毒是当今曼联所说的最常见的环境诱导的疾病。因此，很明显，发现汞和铅等金属的提高排毒策略对人类健康会带来可观的好处。拟议研究的一个核心组成部分是阐明这些金属的生物化学，以促进排毒。该目标将通过使用合成模拟方法来实现，在该方法中，小分子用于模仿生物系统。由于汞和铅的毒性作用在很大程度上是这些金属有效与蛋白质的半胱氨酸残基有效结合的能力的结果，因此将特别强调具有硫供体的配体的应用。 HG-C键的原始分解是细菌中汞排毒的重要组成部分，因此将致力于理解影响这一过程的因素，因此可以为人类应用开发改进的排毒策略。在这方面，重金属中毒的主要治疗方法是螯合疗法，但该技术的有效性远非理想。因此，通过指导努力发现螯合有毒金属的分子，将制定新的螯合治疗策略。例如，将研究具有芳烃基团的多齿配体，因为这些组可能具有分解HG-C键并协调汞的双重目的。此外，将努力用于发现体内促进HG-C键裂解的化合物，并且可以与传统的螯合剂一起使用。这两种方法都很重要，因为它们代表了当前使用的方法的重大进展。 公共卫生相关性：汞和铅是环境中通常遇到的两种最有毒的金属，并且是全球人类健康的严重风险；因此，发现这些金属的提高排毒策略对于公共卫生问题至关重要。拟议研究的一个具体目标是阐明生物系统中有毒金属的化学反应，以便能够发现迫切需要的新排毒策略。因此，拟议的研究与开发基本信息的NIH使命相关，这些信息有助于减轻人类疾病的负担。