Induction of renal metallothionein synthesis by cis-diamminedichloroplatinum(II) in glutathione-depleted mice

I. Nakagawa, T. Yanagiya, N. Imura, A. Naganuma

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Abstract

Effects of glutathione (GSH) depletion on nephrotoxicity of cis-diamminedichloroplatinum(II) (cis-DDP) and induction of renal metallothionein (MT) synthesis elicited by cis-DDP treatment has been studied using mice. Pretreatment with L-buthionine-SR-sulfoximine (BSO) reduced the GSH level in the kidneys to 20% of the control level at the time of cis-DDP administration. Administration of 45 μmol/kg cis-DDP did not change the blood urea nitrogen (BUN) level, determined as an indicator of nephrotoxicity, until 96 h after administration, whereas BSO pretreatment raised the BUN level as early as 48 h after cis-DDP (45 μmol/kg) treatment. The level of renal MT was also increased in the GSH-depleted mice and was changed in parallel with the BUN level after cis-DDP treatment. Level of plasma fibrinogen, one of acute phase proteins, increased by cis-DDP in GSH-depleted mice. The increase was reduced by dexamethasone pretreatment, although the renal MT level increased by BSO and cis-DDP was not changed by dexamethasone pretreatment. These results suggest that the induction of renal MT synthesis by cis-DDP in BSO-pretreated mice was not related with the acute phase responses such as cytokines induction. Although the mechanism of the induction of MT synthesis by cis-DDP in GSH-depleted mice is unclear, it is possible that MT is induced as an antidote against oxidative stress, which may be a major cause for nephrotoxicity of cis-DDP enhanced by GSH depletion.

Original languageEnglish
Pages (from-to)211-219
Number of pages9
JournalJournal of Trace Elements in Experimental Medicine
Volume8
Issue number4
DOIs
Publication statusPublished - 1996 May 1

Keywords

  • Glutathione depletion
  • Metallothionein
  • Nephrotoxicity
  • cis-DDP

ASJC Scopus subject areas

  • Biochemistry

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