Dependence of cadmium-metallothionein nephrotoxicity on glutathione

Acute cadmium-metallothionein (CdMT) injection is frequently used as a mode l 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 inf used over a 24-h period by an osmotic minipump, to cause nephrotoxicity. GS H 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 mu g Cd/kg) that was well tolerated when delive red over a 24-h period became nephrotoxic when GSH synthesis was inhibited by BSO. With depletion of GSH, as little as 0.4 mu g Cd/g renal cortex was sufficient to cause nephrotoxicity after an acute dose of CdMT. While BSO h ad no effect on renal Cd accumulation, pretreatment with GSH reduced renal cortical Cd accumulation by 36%. CdMT nephrotoxicity was enhanced by deplet ing renal GSH, but without increasing renal Cd accumulation, which suggests that intracellular GSH is directly involved in protection against CdMT nep hrotoxicity. Reduced Cd accumulation in the renal cortex following GSH pret reatment suggests an additional extracellular mechanism of GSH protection. it is concluded that GSH status is an important determinant of CdMT nephrot oxicity, with low GSH levels enhancing and high GSH levels reducing its tox icity, and that the mechanism appears to involve both intracellular and ext racellular sites.