gamma-Glutamyl transpeptidase-deficient mice are resistant to the nephrotoxic effects of cisplatin

We have proposed that the nephrotoxicity of cisplatin, a widely used chemot herapy drug, is the result of the binding of cisplatin to glutathione and t he subsequent metabolism of the cisplatin-glutathione complex via a gamma - glutamyl transpeptidase (GGT)-dependent pathway in the proximal tubules. To test die hypothesis that GGT activity is essential for the nephrotoxicity of cisplatin, the effects of cisplatin were examined in wild-type and GGT-d eficient Mice. Mice were treated with 15 mg cisplatin/kg. Five days after t reatment, renal histopathology, blood urea nitrogen levels, serum creatinin e, platinum excretion, and platinum accumulation in the kidney were examine d. Half the mice were supplemented with N-acetylcysteine, which has been sh own to correct low levels of tissue glutathione in GGT-deficient mice. The data show that cisplatin was nephrotoxic in wild-type mice but not in GGT-d eficient mice. The wild-type mice, with and without N-acetylcysteine supple mentation, had significantly elevated levels of blood urea nitrogen, serum creatinine, and renal tubular necrosis. There was no evidence of nephrotoxi city in the GGT-deficient mice regardless of N-acetyl cysteine supplementat ion. No differences in platinum excretion were seen comparing wild-type and GGT-deficient mice, nor was there any significant difference in renal plat inum accumulation. These data suggest that renal cisplatin toxicity is depe ndent on GGT activity, and is not correlated with uptake. The results suppo rt our hypothesis that the nephrotoxicity of cisplatin is the result of the metabolism of the drug through a GGT-dependent pathway.