Strategies for Heavy Metal Detoxification

描述（由申请人提供）：汞和铅在环境中普遍存在，对全世界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和创新的解毒策略。有机汞化合物尤其具有剧毒，20 世纪 50 年代末日本水俣湾附近近 2000 人因食用被甲基汞化合物污染的鱼而死亡，就说明了这一点。此外，在 1970 年代初，使用有机汞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来制作面包而不是种植小麦。日本爆发的甲基汞中毒事件是由于附近化工厂有毒物质释放造成的，而甲基汞化合物也会通过水生环境中天然存在的汞（II）的生物甲基化而进入环境，并在掠食性鱼类体内积累。同样，环境中铅的出现是其当前和以前在电池、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诱发疾病。因此，很明显，发现改进的汞和铅等金属解毒策略将为人类健康带来巨大好处。拟议研究的核心部分是阐明这些有助于解毒的金属的生物化学。这一目标将通过使用合成模拟方法来实现，其中使用小分子来模拟生物系统。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。 Hg-C 键的质子裂解是细菌中汞解毒的重要组成部分，因此将付出大量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，重金属中毒的主要治疗方法是螯合疗法，但该技术的效果还很不理想。因此，将通过努力发现更有效地螯合有毒金属的分子来开发螯合疗法的新策略。例如，将研究以芳烃硫醇基团为特征的多齿配体，因为这些基团可能具有裂解 Hg-C 键和配位汞的双重目的。此外，我们将致力于发现在体内促进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，因为它们代表了当前使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.