Role of metallothionein in protection against renal oxidative stress induced by cis-diamminedichloroplatinum (II) in glutathione-depleted mice

The protective role of metallothionein (MT) against renal lipid peroxidation caused by administration of cis-diamminedichloroplatinum (II) (cis-DDP) was examined in glutathione (GSH)-depleted mice. Pretreatment with DL-buthionine-SR-sulfoximine (BSO), an inhibitor of GSH synthesis, 4 hr prior to injection of a subtoxic dose of cis-DDP (45 μmol/kg) significantly induced renal toxicity of this anticancer drug evaluated by an increase in blood urea nitrogen (BUN) levels. Renal levels of thiobarbiturate-reactive substances (TBA-RS), determined as an indicator for lipid peroxidation, were also significantly increased in BSO-treated mice by cis-DDP in advance of the increase in BUN values. The BSO-enhanced renal lipid peroxidation induced by cis-DDP was found to be attenuated by pre-administration of zinc chloride, an inducer of MT synthesis. Binding of platinum to MT in the kidneys of mice after cis-DDP administration was not increased by pretreatment with zinc chloride. A significant decrease in concentration of preinduced-MT was observed after administration of cis-DDP. This result suggests that MT may prevent the lipid peroxidation by scavenging free radicals generated by cis-DDP, but not by binding directly to cis-DDP or its metabolites, in GSH-depleted mice. The present findings support the view that MT may substitute for GSH as a scavenger of radicals produced by cis-DDP.