Gamma-glutamyl transpeptidase-deficient mice are resistant to the nephrotoxic effects of cisplatin.
We have proposed that the nephrotoxicity of cisplatin, a widely used chemotherapy drug, is the result of the binding of cisplatin to glutathione and the subsequent metabolism of the cisplatin-glutathione complex via a gamma-glutamyl transpeptidase (GGT)-dependent pathway in the proximal tubules. To test the hypothesis that GGT activity is essential for the nephrotoxicity of cisplatin, the effects of cisplatin were examined in wild-type and GGT-deficient mice. Mice were treated with 15 mg cisplatin/kg. Five days after treatment, renal histopathology, blood urea nitrogen levels, serum creatinine, platinum excretion, and platinum accumulation in the kidney were examined. Half the mice were supplemented with N-acetylcysteine, which has been shown 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-deficient mice. The wild-type mice, with and without N-acetylcysteine supplementation, had significantly elevated levels of blood urea nitrogen, serum creatinine, and renal tubular necrosis. There was no evidence of nephrotoxicity in the GGT-deficient mice regardless of N-acetyl cysteine supplementation. No differences in platinum excretion were seen comparing wild-type and GGT-deficient mice, nor was there any significant difference in renal platinum accumulation. These data suggest that renal cisplatin toxicity is dependent on GGT activity, and is not correlated with uptake. The results support our hypothesis that the nephrotoxicity of cisplatin is the result of the metabolism of the drug through a GGT-dependent pathway.
Hanigan
M H
MH
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. marie-hanigan@ouhsc.edu
Lykissa
E D
ED
Townsend
D M
DM
Ou
C N
CN
Barrios
R
R
Lieberman
M W
MW
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000506:poisoning*; D001806:Blood Urea Nitrogen; D001835:Body Weight; D002945:Cisplatin / Q000506:poisoning*; D003404:Creatinine / Q000097:blood; D004351:Drug Resistance; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010984:Platinum / Q000378:metabolism / Q000652:urine; D012016:Reference Values; D005723:gamma-Glutamyltransferase / Q000172:deficiency* / Q000235:genetics
D000970:Antineoplastic Agents; D010984:Platinum; D003404:Creatinine; D005723:gamma-Glutamyltransferase; D002945:Cisplatin; D000111:Acetylcysteine