Metallothionein induction in mouse tissues by cis-dichlorodiammineplatinum(II) and its hydrolysis products

cis-Dichlorodiammineplatinum(II) (cis-DDP) doubled the amount of metallothioneins (MTs) in the livers and kidneys of BALB/c mice when injected i.p. in a single high dose of 30 mumol/kg (9 mg/kg). Two such doses given 17 h apart increased hepatic MTs 5-fold and also increased the relative rate of incorporation of radiolabelled cyst(e)ine into hepatic MTs. Hydrolysed cis-DDP was more effective than cis-DDP, increasing MT-bound zinc 27-fold and [3H]cysteine incorporation 6-fold in liver while doubling each of these in kidney. The MTs from the livers of mice treated with cis-DDP bound zinc, copper and platinum in ratios of 5:1:0.3, respectively, similar to those in whole liver and its soluble fraction, indicating that MTs do not selectively sequester platinum under these circumstances. The effects of cis-DDP on zinc and copper levels in serum, liver and kidney suggest that induction of MTs by cis-DDP is not mediated by displacement of endogenous zinc. Indirect induction by corticosteroids secreted in a stress response to cis-DDP is also an unlikely cause. cis-DDP, probably in a hydrolysed form, can therefore induce and bind to MTs in normal tissues, particularly when given at repeated high dosage.