Inhibition of gamma-glutamyl transpeptidase activity by acivicin in vivo protects the kidney from cisplatin-induced toxicity.
Cisplatin [cis-dichlorodiammineplatinum(II)] is a widely used chemotherapeutic drug that is toxic to the proximal tubule cells of the kidney. gamma-Glutamyl transpeptidase (GGT) is localized to the luminal surface of the renal proximal tubules. GGT catalyzes the initial step in the metabolism of glutathione-conjugated drugs to mercapturic acids, some of which are severely nephrotoxic. We proposed that the nephrotoxicity of cisplatin was dependent on the cleavage of a cisplatin-glutathione conjugate by GGT. To test this hypothesis, renal GGT activity was blocked in male Sprague-Dawley rats by acivicin, a non-competitive inhibitor of GGT. Treatment with cisplatin alone caused extensive acute necrosis of the proximal tubules, but the proximal tubule cells appeared normal in rats treated with acivicin prior to cisplatin. Blood urea nitrogen and serum creatinine levels confirmed the protective effect of acivicin. Glutathione is a physiological substrate for GGT. Administration of an 83-fold excess of glutathione 30 min prior to cisplatin also inhibited cisplatin-induced nephrotoxicity. These data provide important new evidence that a large bolus of glutathione blocks the nephrotoxicity of cisplatin by competitively inhibiting GGT. These results indicate that cisplatin is conjugated to glutathione in vivo. The platinum-glutathione conjugate is nontoxic until metabolized by the proximal tubule cells. Formation of the nephrotoxic derivative of cisplatin requires GGT activity.
Department of Cell Biology, University of Virginia Health Sciences Center, Charlottesville 22908.
M H
MH
Hanigan
B C
BC
Gallagher
P T
PT
Taylor
M K
MK
Large
D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004435:Eating; D005978:Glutathione / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors*
D007555:Isoxazoles; D003404:Creatinine; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin; D002945:Cisplatin