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.
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