The role of metallothionein in the reduction of cisplatin-induced nephrotoxicity by Bi 3+-pretreatment in the rat in vivo and in vitro: Are antioxidant properties of metallothionein more relevant than platinum binding?

Abstract

Nephrotoxicity induced by cisplatin (CDDP) was reported to be reduced by Bi 3+-pretreatment, which selectively induces renal metallothionein (MT). In the present study renal MT had increased to 250% of control in rats that received bismuth subnitrate (50 μmol/kg/day, orally) for 8 days. In vitro experiments demonstrated that the reduction of CDDP-induced toxicity is a renal effect: in proximal tubular cells (PTC) isolated from Bi 3+-treated rats the toxicity of CDDP, and also of HgCl 2, CdCl 2 and p-aminophenol, was reduced as compared to PTC from untreated rats. In contrast to the reduction in CDDP, Hg 2+ and Cd 2+ toxicity, the reduction in p-aminophenol toxicity cannot be explained by the metal-binding properties of MT. MT was reported to act as a free radical scavenger, which may explain our observation since p-aminophenol toxicity is thought to be a consequence of the generation of oxygen radicals. In vivo experiments showed that the overall renal Pt-content as well as the Pt bound to renal MT is lower in Bi 3+-pretreated rats than in untreated rats, 24 hr after administration of CDDP (12 mg/kg), suggesting that the reduction in nephrotoxicity is not due to increased binding of Pt 2+ to renal MT. Renal superoxide dismutase (SOD) activity was increased in rats that had only recieved CDDP. Such a rise in SOD may result from peroxidative damage caused by exposure to CDDP. The fact that SOD was not elevated in rats that recieved Bi 3+ prior to CDDP suggests that (i) peroxidation contributes to CDDP-induced nephrotoxicity and (ii) the anti-oxidant properties of MT are responsible for the reduction of this toxicity.