The objectives of the proposed work are (1) the development of a series of compounds capable of mobilizing aged cadmium deposits from the kidney, liver and other organs, (2) the determination of the conditions under which this must be carried out so that these organs can regain part or all of their normal functioning capacity and (3) the determination of the basic processes at the cellular level which are involved when cadmium mobilization occurs under the influence of our newly developed chelating agents. The biological parameters, determined in the studies listed below, will be used concurrently to develop structure-activity relationships which will serve as a guide for our efforts in the synthesis of new chelating agents for cadmium intoxication. The compounds which will mobilize aged cadmium deposits which we have developed during the past year (mostly dithiocarbamates with moderately polar substituents) as well as chelating agents which are to be newly synthesized will be used in a series of studies as follows. (a) Studies to determine how to mobilize aged cadmium deposits from the kidney so that kidney functioning returns to normal as the cadmium levels of the kidney are reduced. Kidney function will be followed by a determination of parameters indicative of cadmium induced kidney damage: urinary Beta2-microglobulin, urinary osmolarity, blood urea nitrogen values and related measures of such damage. (b) Comparative studies involving cell cultures, whole animals, and isolated metallothionein to obtain information on the basic cellular processes involved in the mobilization of aged cadmium deposits. These will use a variety of techniques i.e. standard cell culture techniques plus flow fluorocytometry, Cd n.m.r. studies on the cadmium transfer from metallothionein to chelating agent, as well as standard animal techniques. Pathological evaluations will be carried out as an integral part of the whole animal studies.
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