Strategies for Heavy Metal Detoxification

描述（由申请人提供）：汞和铅在环境中普遍存在，对全世界的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。20世纪50年代末，日本水俣湾附近近2000人因食用了被甲基汞化合物污染的鱼类而死亡，这就说明了有机汞化合物的毒性特别强。此外，在1970年代初，使用有机化合物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。虽然日本甲基汞中毒的爆发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汞（II）的生物甲基化而进入环境，并在食肉鱼类中积累。同样，铅在环境中的出现是其目前和以前广泛使用的结果，例如在电池、汽油、管道和油漆中，因此铅中毒是当今美国儿童中最常见的由环境引起的疾病。因此，很明显，发现改善汞和铅等金属的排毒策略将对人类健康大有裨益。拟议研究的一个中心组成部分将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小分子来模拟生物系统的合成模拟方法来实现。由于汞和铅的毒性作用主要是由于这些金属与蛋白质的半胱氨酸残基有效结合的能力，因此将特别强调以硫供体为特征的配体的应用。Hg-C键的原生裂解是细菌中汞解毒的重要组成部分，因此需要大量的努力来了解影响这一过程的因素，以便开发出适用于人类的改进解毒策略。在这方面，重金属中毒的主要治疗方法是螯合治疗，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直接努力发现更有效地螯合有毒金属的分子来开发。例如，多齿配体的特点是烯硫醇基团将被研究，因为这些基团可能具有双重目的，既可以切割Hg-C键，又可以协调汞。此外，我们还将努力寻找能够在体内促进Hg-C键裂解的化合物，并将其与传统螯合剂联合使用。这两种方法都很重要，因为它们代表了目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.