CADMIUM CHELATION THERAPY:DEV NEW AGENTS TO PREVENT/TREAT HEAVY METAL POISONING

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。镉的螯合疗法：开发预防或治疗重金属中毒的新药物对镉的细胞反应包括代谢变化、金属结合蛋白的隔离和细胞程序性死亡或凋亡。镉在分子水平上的影响还没有得到很好的证明。一份报告描述了镉如何抑制三角洲氨基乙酰丙酸脱氢酶，这种酶催化两个三角洲氨基乙酰丙酸分子缩合产生胆红素原(一种血红素前体)，导致发育受阻。另一项研究描述了这些重金属是如何导致氧化损伤导致癌症的。这些作者发现，与细胞抗氧化剂有亲和力的非氧化还原活性重金属(Cd、Pb、Hg和As)的存在破坏了抗氧化剂/氧化剂的平衡，从而对细胞成分如脂类、蛋白质和DNA发生了不利的氧化。我们建议合成、表征和测试亲水性黄原酸酯、二硫代氨基甲酸酯和硫酮类化合物对镉的吸附选择性和效率。在项目过程中将测试以下假设：1)确定二硫代氨基甲酸钾、黄原酸钾和硫酮是水溶性的；2)确定这些分子在钙和镁离子存在下是否能有效和选择性地与镉结合；3)确定候选镉隔离剂的细胞毒性水平；以及4)确定候选隔离分子是否影响细胞中的蛋白质表达。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cadmium chelation therapy: Development of new agents to prevent or treat heavy metal poisoning Cellular responses to cadmium include metabolic changes, sequestering by metal binding proteins and programmed cell death or apoptosis. The effects of the presence of cadmium at the molecular level have been less well documented. One report described how cadmium inhibited delta-aminolevulinate dehydrogenase, an enzyme that catalyzes the condensation of two delta-aminolevulinic acid molecules to yield porphobilinogen (a heme precursor), leading to disrupted development. Another study described how such heavy metals induce oxidative damage leading to cancer. These authors found that the presence of non-redox active heavy metals (Cd, Pb, Hg and As) with an affinity for cellular antioxidants disrupted the antioxidant/oxidant balance such that adverse oxidation occurred to cellular components such lipids, proteins and DNA. We propose to synthesize, characterize and test the cadmium-sequestering selectivity and efficiency of the hydrophilic xanthates, dithiocarbamates and thioketones. The following hypotheses will be tested during the course of the project: 1) To determine that potassium dithiocarbamates, potassium xanthates and thioketones are water soluble; 2) To determine whether these molecules will bind cadmium efficiently and selectively in the presence of calcium and magnesium ions; 3) To determine the level of cytotoxicity of candidate cadmium-sequestering agents; and 4) To determine whether the candidate sequestering molecules affect protein expression in cells.