The propsed research will characterize the action of a novel group of antagonists to the toxic effects of cadmium. Cadmium is a toxic trace element that presents a potentially serious health hazard to humans and our environment. It accumulates in the kidneys and liver of humans & animlas, with an estimated half life in humans of 20-40 years, and can cause bone and kidney damage in exposed individuals. Preliminary in vitro experiments, utiliziang an automated cell growth cytotoxicity assay, have indicated that a novel group of diverse chemical agents can protect mouse fibroblasts from Cd2+ toxicity. These agents, which include dimethyl sufoxide, Na butyrate, hypoxanithine, hexamethylene bisacetamide, N-methyl formamide, N,N'-dimethyl formamide, hemin, ouabain and dimethyl acetamide, also have in common the capacity to induce differentiation in vitro in Friend erythroleukemia cells. The process of differentiation induction in vitro, not yet understood, is relevant to the cancer problem, and several of these differentiation inducers are under investigation as potential cancer chemotherapeutic agents. This proposal is designed to characterize the protection against Cd2+ toxicity provided by these agents in vitro, through a series of studies on their mechanism(s) of action, and to determine the generality of these protective effects. Mechanistic studies will include the measurement of metallothionein induction, cadmium transport and accumulation, glutathione concentrations and the presence of cadmium binding proteins in cells treated with these cadmium antagonists. The generality of the antagonism to cadmium toxicity exerted by these agents will be explored in studies with human epithelial cells in culture and in experiments with rats, which will be undertaken to determine whether these differentiation inducers can protect animals from the acute hepatotoxicity and chronic nephrotoxicity of cadmium.
