The broad, long-term objective of the proposed study is the development of new chelating agents which are superior to any previously reported for the treatment of cadmium intoxication via reduction of organ levels of cadmium, especially in the liver and kidney. Our goal is to obtain compounds which are effective in rodents when administered at a level of 40 micro mol/kg and which remove renal and hepatic cadmium without causing any transport of cadmium to the brain, any increase in the cadmium content in any other organ, or any significant adverse effects in any organ. Our results indicate that the most promising compounds to pursue in these studies are dithiocarbamates and vicinal dithiols. These new compounds are to remove cadmium from the kidneys in such a manner that, when starting with kidneys which exhibit renal dysfunction due to accumulated cadmium (100-200 ppm), treatment with the new chelating agents will induce a large reduction in the cadmium levels and a concurrent return toward more normal renal function. For the most effective compounds of each type, more detailed studies will be carried out on the acute and chronic toxicity as well as in vivo metabolism and disposition. We plan to expand the rational drug design rules we have previously developed for use in the design of optimally effective cadmium mobilizing agents. We will also expand our investigation of the routes by which chelating agents gain access to intracellular sites in various organs; our preliminary studies show that for the most effective of our new chelating agents an organic anion transport system is used for this purpose in both the kidney and the liver. A more detailed understanding of such pathways will greatly facilitate the design of new chelating agents for the removal of cadmium from various organs in which it accumulates. It is also planned to continue studies on the basic mechanisms of the various steps involved in the cadmium mobilization process in order to determine how it might be most effectively accelerated.
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