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

Danyelle M Townsend1, Kenneth D Tew, Lin He

  • 1Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, 173 Ashley Avenue, P.O. Box 250505, Charleston, SC 29425, USA.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|September 30, 2008
PubMed

Insights

Glutathione S-transferase Pi (GSTP) significantly impacts cisplatin nephrotoxicity. Higher GSTP levels in male mice correlated with increased kidney damage, a difference eliminated in GSTP-deficient mice.

Area of Science:

  • Biochemistry
  • Toxicology
  • Pharmacology

Background:

  • Cisplatin is a widely used chemotherapy agent.
  • Nephrotoxicity is a major dose-limiting side effect of cisplatin.
  • The exact mechanisms of cisplatin-induced kidney damage are not fully understood, particularly the role of specific enzymes.

Purpose of the Study:

  • To investigate the role of glutathione S-transferase Pi (GSTP) in the bioactivation of cisplatin.
  • To determine if GSTP influences cisplatin-induced nephrotoxicity.
  • To explore the contribution of GSTP to sex-dependent differences in cisplatin toxicity.

Main Methods:

  • Treatment of wild-type and GSTP-deficient (GstP1/P2 null) mice with cisplatin.
  • Evaluation of renal toxicity and damage 5 days post-treatment.
  • Comparison of GSTP expression levels between male and female wild-type mice, particularly in the liver.

Main Results:

  • Renal damage was most severe in wild-type male mice compared to females.
  • Wild-type male mice exhibited approximately 10-fold higher hepatic GSTP expression than females.
  • In GstP1/P2 null mice, the gender-based difference in cisplatin toxicity was abolished.

Conclusions:

  • GSTP expression is a critical determinant in cisplatin-induced nephrotoxicity.
  • Hepatic GSTP contributes to the formation of nephrotoxic platinum-glutathione conjugates.
  • GSTP levels play a significant role in the sex-dependent differences observed in cisplatin nephrotoxicity.

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