Dependence of cadmium-metallothionein nephrotoxicity on glutathione

Acute cadmium-metallothionein (CdMT) injection is frequently used as a model to study the mechanism of chronic Cd-induced nephrotoxicity. The purpose of this study was to investigate the relationship between glutathione (GSH) status and the ability of CdMT, either administered as a bolus dose or infused over a 24-h period by an osmotic minipump, to cause nephrotoxicity. GSH levels were modulated by pretreatment with either buthionine sulfoximine (BSO) or GSH. BSO enhanced while GSH suppressed acute CdMT nephrotoxicity. An infused dose of CdMT (150 microg Cd/kg) that was well tolerated when delivered over a 24-h period became nephrotoxic when GSH synthesis was inhibited by BSO. With depletion of GSH, as little as 0.4 microg Cd/g renal cortex was sufficient to cause nephrotoxicity after an acute dose of CdMT. While BSO had no effect on renal Cd accumulation, pretreatment with GSH reduced renal cortical Cd accumulation by 36%. CdMT nephrotoxicity was enhanced by depleting renal GSH, but without increasing renal Cd accumulation, which suggests that intracellular GSH is directly involved in protection against CdMT nephrotoxicity. Reduced Cd accumulation in the renal cortex following GSH pretreatment suggests an additional extracellular mechanism of GSH protection. It is concluded that GSH status is an important determinant of CdMT nephrotoxicity, with low GSH levels enhancing and high GSH levels reducing its toxicity, and that the mechanism appears to involve both intracellular and extracellular sites.