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.
Farnworth
P G
PG
Experimental Chemotherapy Unit, Cancer Institute, Melbourne, Australia.
Hillcoat
B L
BL
Roos
I A
IA
D000818:Animals; D002850:Chromatography, Gel; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis* / Q000302:isolation & purification; D051379:Mice; D008807:Mice, Inbred BALB C; D012016:Reference Values; D013431:Sulfates / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology; D019287:Zinc Sulfate
D013431:Sulfates; C034297:diamminediaqua platinum(II); D019287:Zinc Sulfate; D008668:Metallothionein; D015032:Zinc; D002945:Cisplatin