The mechanism of renal uptake of nephrotoxic heavy metals such as HgCI2 and NaAsO2 is not clear. The metals are known to react with endogenous sulfhydryls such as glutathione (GSH), so metal-GSH conjugates may be delivered to the kidney. To study this possibility, renal cortical slices from male New Zealand white rabbits were incubated with 104 M HgCI2 or 10-3 M NaAsO2 ± stoichiometric amounts (1-3x) of GSH; or synthetic metal-GSH conjugates [104 M Hg(SG)2 or 1 M As(SG)31. Incubations were performed at 370C in DME-F12 buffer (95/5 02/CO2) for 8 hr. Hg(SG)2 reduced slice K+/DNA content, as an indicator of viability, significantly less than HgCI2. As(SG)3 exhibited a 2-hr delay in K+/DNA content reduction compared to NaAsO2. This delay in toxicity was not correlated to changes in uptake. Arsenic and mercury accumulation, determined by protoninduced X-ray emission, were also identical between the metal salts and the metal-GSH conjugates. Exogenous GSH decreased HgCI2 cytotoxicity and was correlated to a decrease in Hg accumulation in the slice. Exogenous GSH had limited if any protective effects against cytotoxicity by NaAsO2 and a decrease in As accumulation was not observed. Complex metal-GSH interactions appear to exist and impact on the uptake and toxicity of these metals. -Environ Health Perspect 103(Suppl 1): 81-84 (1995)