Cisplatin nephrotoxicity is mediated by gamma glutamyltranspeptidase, not via a C-S lyase governed biotransformation pathway

Richard D. Wainford, Richard J. Weaver, Keith N. Stewart, Paul Brown, Gabrielle M. Hawksworth

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Abstract

Cisplatin exhibits dose-limiting nephrotoxicity in rodents and man. This study investigates the mechanism of cisplatin nephrotoxicity in vivo and in an in vitro model system. Nephrotoxicity was induced in rats (6 mg/kg cisplatin i.p.) and mice (10 mg/kg cisplatin i.p.). Cisplatin administration significantly elevated blood urea nitrogen (BUN) and serum creatinine in male Sprague Dawley rats day 5 post-treatment (BUN Delta + 28 +/- 5 mu mol/ml; serum creatinine Delta +/- 1084 nmol/ml, P < 0.05) and in male C57BL6 mice day 4 post-treatment (BUN Delta + 21 +/- 4 mu mol/ml; serum creatinine Delta + 81 +/- 5 nmol/ml, P < 0.05). Nephrotoxicity was confirmed by histological analysis that revealed significant damage to the proximal tubules of cisplatin-versus saline vehicle-treated animals. Inhibition of gamma glutamyltranspeptidase prevented cisplatin nephrotoxicity in Sprague Dawley rats (day 5 BUN Delta + 1 +/- 2 mu mol/ml; serum creatinine A + 8 +/- 4 mu mol/ml) and C57131.6 mice (day 4 BUN Delta + 1 +/- 0.8 mu mol/ml: serum creatinine Delta - 1 +/- 2 nmol/ml), but not cellular toxicity in rat proximal tubular (RPT) or human proximal tubular (HPT) cultures. Inhibition of aminopeptidase N (AP-N) or renal dipeptidase (RDP) in male Sprague Dawley rats, or in RPT and HPT cell cultures, did not reduce cisplatin toxicity. In contrast to published findings inhibition of C-S lyase did not prevent the nephrotoxicity of cisplatin in vivo or cellular toxicity in vitro. These data demonstrate that the biotransformation enzymes AP-N, RDP and C-S Iyase are not implicated in the metabolism of cisplatin to a nephrotoxic metabolite as has been previously hypothesised. Instead, our data demonstrate that gamma glutarnyltranspepticlase is a key enzyme involved in mediating cisplatin nephrotoxicity, which potentially acts to cleave cisplatin-GSH conjugates to a toxic metabolite.(C) 2008 Elsevier Ireland Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)184-193
Number of pages10
JournalToxicology
Volume249
Issue number2-3
Early online date21 May 2008
DOIs
Publication statusPublished - 30 Jul 2008

Keywords

  • cisplatin nephrotoxicity
  • in vivo
  • rat proximal tubular cell cultures
  • human proximal tubular cell cultures
  • proximal tubular cells
  • conjugate beta-lyase
  • transpeptidase-deficient mice
  • glutamyl-transpeptidse
  • primary cultures
  • platinum complexes
  • induced toxicity
  • in-vivo
  • intracellular glutathione
  • liquid-chromatography

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