NEPHROTOXICITY OF CADMIUM-METALLOTHIONEIN - PROTECTION BY ZINC AND ROLE OF GLUTATHIONE

Chronic cadmium (Cd) exposure can cause renal proximal tubular dysfunc tion resulting from the release of Cd metallothionein (CdMT) from the liver and its accumulation and degradation in the renal tubular epithe lial cells. Pretreatment with zinc (Zn) can protect against acute CdMT nephrotoxicity. While induction of MT by Zn plays a part in Zn protec tion, other factors, such as glutathione (GSH), may also be involved b ecause protection is offered even in MT-null mice. The present study w as designed to investigate the involvement of GSH in Zn protection aga inst acute CdMT nephrotoxicity. The study was carried out in MT-null m ice to remove the induction of MT by Zn as a confounding variable. Thr ee approaches were used to modulate renal cortex GSH levels: buthionin e sulfoximine (BSO) was administered to inhibit GSH synthesis, and GSH and Zn were administered to increase the GSH levels. Both GSH and Zn were effective in protecting against CdMT nephrotoxicity. Elevation in renal cortex GSH levels, however, was not essential for Zn protection , as a low dose of Zn that caused no significant increase in renal GSH also protected against CdMT. On the other hand, maintenance of normal GSH status was essential for Zn protection, as inhibition of GSH synt hesis abolished this protection. Both GSH and Zn reduced the accumulat ion of Cd as well as MT in the renal cortex, with Zn causing greater r eduction in Cd accumulation than that of MT. The relative intracellula r distribution of Cd was unaltered. These results suggest that in MT-n ull mice Zn protects against CdMT nephrotoxicity by possibly displacin g some of the Cd from CdMT as well as reducing the uptake of CdMT, and that this protection requires the maintenance of normal GSH status, ( C) 1998 Academic Press.