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 peroxi dation caused by administration of cis-diammine-dichloroplatinum (II) (cis-DDP) was examined in glutathione (GSH)-depleted mice. Pretreatmen t with DL-buthionine-SR-sulfoximine (BSO), an inhibitor of GSH synthes is, 4 hr prior to injection of a subtoxic dose of cis-DDP (45 mu mol/k g) significantly induced renal toxicity of this anticancer drug evalua ted by an increase in blood urea nitrogen (BUN) levels. Renal levels o f thiobarbiturate-reactive substances (TBA-RS), determined as an indic ator 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 chlori de. A significant decrease in concentration of preinduced-MT was obser ved after administration of cis-DDP. This result suggests that MT may prevent the lipid peroxidation by scavenging free radicals generated b y 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 ma y substitute for GSH as a scavenger of radicals produced by cis-DDP.