Strategies for Heavy Metal Detoxification

描述(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威胁。拟议研究的目的是为这些金属开发新的创新解毒策略。有机汞化合物尤其剧毒，20世纪50年代末，日本水手湾附近近2000人死亡，当时当地居民食用被甲基汞化合物污染的鱼，就证明了这一点。此外，20世纪70年代初，有机汞作为杀虫剂的使用导致伊拉克约500人死亡，当时经过这些杀虫剂处理的小麦种子被用来制作面包，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，但甲基汞化合物也是通过水环境中自然产生的汞(II)的生物甲基化引入环境中，并在捕食性鱼类体内积累。同样，铅在环境中的出现是目前和以前在电池、汽油、管道和油漆等领域广泛使用的结果，因此铅中毒是当今美国儿童中最常见的环境引起的疾病。因此，显然，发现汞和铅等金属的改进解毒策略将对人类健康有相当大的好处。拟议研究的一个中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模拟方法来实现，在该方法中，小分子被用来模拟生物系统。由于汞和铅的毒性效应在很大程度上是这些金属与蛋白质的半胱氨酸残基有效结合的能力的结果，因此将特别强调以硫供体为特征的配体的应用。汞-碳键的蛋白裂解是细菌汞解毒的重要组成部分，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改进的解毒策略。对此，目前治疗重金属中毒的主要方法是螯合疗法，但这项技术的效果还远不理想。因此，通过努力发现更有效地螯合有毒金属的分子，将开发新的螯合治疗策略。例如，将研究以芳硫醇为特征的多齿配体，因为这些基团可能具有断裂汞-碳键和配位汞的双重目的。此外，还将致力于发现在体内促进汞-碳键断裂的化合物，并可能与传统的螯合剂一起使用。这两种方法都很重要，因为它们代表着相对于目前采用的方法的重大进步。

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.