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

Toxicology. 2008 Jul 30;249(2-3):184-93. doi: 10.1016/j.tox.2008.05.006. Epub 2008 May 21.


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 micromol/ml; serum creatinine Delta+108+/-4 nmol/ml, P<0.05) and in male C57BL6 mice day 4 post-treatment (BUN Delta+21+/-4 micromol/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 micromol/ml; serum creatinine Delta+8+/-4 nmol/ml) and C57BL6 mice (day 4 BUN Delta+1+/-0.8 micromol/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 lyase are not implicated in the metabolism of cisplatin to a nephrotoxic metabolite as has been previously hypothesised. Instead, our data demonstrate that gamma glutamyltranspeptidase is a key enzyme involved in mediating cisplatin nephrotoxicity, which potentially acts to cleave cisplatin-GSH conjugates to a toxic metabolite.

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / toxicity*
  • Biotransformation
  • Body Weight / drug effects
  • Cell Separation
  • Cisplatin / metabolism
  • Cisplatin / toxicity*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / pathology
  • Kidney Diseases / physiopathology
  • Kidney Function Tests
  • Kidney Tubular Necrosis, Acute / chemically induced
  • Kidney Tubular Necrosis, Acute / pathology
  • Lyases / antagonists & inhibitors
  • Lyases / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Rats
  • Rats, Sprague-Dawley
  • Species Specificity
  • gamma-Glutamyltransferase / antagonists & inhibitors
  • gamma-Glutamyltransferase / physiology*


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • gamma-Glutamyltransferase
  • Lyases
  • carbon-sulfur lyase
  • Cisplatin