Role of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity

Biomed Pharmacother. 2009 Feb;63(2):79-85. doi: 10.1016/j.biopha.2008.08.004. Epub 2008 Sep 7.


One of the dose-limiting toxicities of cisplatin is nephrotoxicity. Renal toxicity is localized to quiescent proximal tubule cells, where the formation of DNA-adducts cannot account for the dose-limiting toxicity. Our earlier results have shown that a glutathione conjugate of cisplatin is metabolized to a nephrotoxicant via gamma-glutamyl transpeptidase (GGT) and a cysteine S-conjugate beta-lyase. The present study was designed to evaluate the potential role of glutathione S-transferase Pi (GSTP) in the initial steps of the bioactivation of cisplatin. Wild-type mice and mice deficient in both murine GSTP genes (GstP1/P2) were treated with cisplatin. Toxicity in both male and female mice was evaluated 5 days after treatment and renal damage was most severe in wild-type male mice. Wild-type males have approximately 10-fold higher levels of GSTP expression in the liver than females, suggesting that hepatic GSTP in the wild-type males contributed to the formation of the nephrotoxic platinum-glutathione conjugate. In GstP1/P2 null mice the gender difference in toxicity was eliminated. Our data show that GSTP expression is a determinant in cisplatin-induced nephrotoxicity and its levels contribute to sex-dependent differences.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / toxicity*
  • Carbon-Sulfur Lyases / metabolism
  • Cisplatin / administration & dosage
  • Cisplatin / metabolism
  • Cisplatin / toxicity*
  • Female
  • Gene Expression Regulation, Enzymologic
  • Glutathione S-Transferase pi / genetics
  • Glutathione S-Transferase pi / metabolism*
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Severity of Illness Index
  • Sex Factors
  • gamma-Glutamyltransferase / metabolism


  • Antineoplastic Agents
  • gamma-Glutamyltransferase
  • Glutathione S-Transferase pi
  • Gstp1 protein, mouse
  • Carbon-Sulfur Lyases
  • cysteine-S-conjugate beta-lyase
  • Cisplatin