Cisplatin nephrotoxicity: inhibition of gamma-glutamyl transpeptidase blocks the nephrotoxicity of cisplatin without reducing platinum concentrations in the kidney.
OBJECTIVE
Inhibition of gamma-glutamyl transpeptidase activity by acivicin or a large bolus of intravenous glutathione blocks the nephrotoxicity of cisplatin. The purpose of this study was to determine whether these compounds inhibit nephrotoxicity by reducing the amount of platinum retained by the kidney.


METHODS
The platinum concentration in urine and kidney of cisplatin-treated rats was determined by graphite furnace atomic absorption spectroscopy. Tissues from three experimental groups of rats were analyzed. The first group was treated with a nephrotoxic dose of cisplatin. The second group was treated with acivicin before cisplatin. The third group received a bolus of glutathione before cisplatin. Urine collected for 3 hours after the injection of cisplatin and kidney tissue from animals 5 days after treatment were analyzed for platinum content.


RESULTS
Urine from animals pretreated with acivicin had the same concentration of platinum as that of control animals treated with cisplatin alone. Analysis of kidney tissue, blood urea nitrogen and serum creatinine 5 days after treatment showed that pretreatment with acivicin or glutathione blocked the nephrotoxicity of cisplatin. However, these agents did not alter the concentration of platinum in the kidney.


CONCLUSIONS
The data in this study reveal that pretreatment with acivicin or glutathione does not block the uptake of platinum into the kidney nor do these agents reduce the concentration of platinum retained by the kidney. The mechanism by which these agents may inhibit the nephrotoxicity of cisplatin is discussed.
Hanigan
M H
MH
Department of Cell Biology, University of Virginia, Charlottesville 22908, USA.
Gallagher
B C
BC
Taylor
P T
PT
D000818:Animals; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005978:Glutathione / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010984:Platinum / Q000378:metabolism* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007555:Isoxazoles; D010984:Platinum; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin; D002945:Cisplatin