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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。镉螯合疗法：预防或治疗重金属中毒的新药物的开发细胞对镉的反应包括代谢变化、金属结合蛋白的隔离和程序性细胞死亡或凋亡。镉在分子水平上的影响还没有得到很好的记录。一份报告描述了镉如何抑制δ -氨基乙酰丙酸脱氢酶，这种酶催化两个δ -氨基乙酰丙酸分子缩合产生卟啉胆色素原（一种血红素前体），导致发育中断。另一项研究描述了这些重金属是如何引起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（如脂质、蛋白质和DNA）发生了不利的氧化。本研究拟合成亲水性黄原酸盐、二硫代氨基甲酸酯和硫酮类化合物，并对其吸附镉的选择性和效率进行表征和测试。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)在钙、镁离子存在的情况下，确定这些分子是否会有效和选择性地结合镉；3)测定候选镉隔离剂的细胞毒性水平；4)确定候选隔离分子是否影响细胞中的蛋白表达。

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.