Exogenous glutathione decreases cellular cadmium uptake and toxicity

The effect of intracellular glutathione (GSH) on cadmium metabolism and toxicity has been extensively investigated. However, little is known regarding the effect of extracellular GSH on cellular cadmium responses. Therefore, this study was conducted to investigate the effect of exogenously added GSH on cadmium toxicity in normal rat kidney fibroblasts (NRK-49F). Exponentially growing NRK-49F cells were arrested by serum deprivation and then stimulated with epidermal growth factor (EGF). CdCl2, at concentrations that range from 0.25 to 2 microM, was found to inhibit, in a dose-dependent fashion, the EGF-induced DNA synthesis (as judged by [3H]thymidine incorporation) in the cells. A long-term survival assay revealed that CdCl2 above 1 microM was toxic to the cells. Exogenous GSH had a dose-dependent antagonistic effect on cadmium inhibition of EGF-induced DNA synthesis, and 1 mM GSH was found to block completely cadmium inhibition of both EGF-induced DNA synthesis and cell survival. Exogenously added GSH did not increase intracellular GSH levels but decreased cadmium accumulation by the cells. This decrease was primarily caused by a reduced cadmium uptake. Further studies indicated that exogenous GSH would form a complex with cadmium outside of the cells preventing cellular cadmium uptake. This may explain the mechanism of action of the exogenous GSH in cytoprotection against cadmium. The results also suggested a practical potential for GSH as a cadmium chelator. If GSH were coadministered with a cadmium mobilizer and a gamma-glutamyl transpeptidase inhibitor, it could enhance cadmium excretion from the body.