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 chemothe rapeutic drug that is toxic to the proximal tubule cells of the kidney . gamma-Glutamyl transpeptidase (GGT) is localized to the luminal surf ace of the renal proximal tubules. GGT catalyzes the initial step in t he metabolism of glutathione-conjugated drugs to mercapturic acids, so me of which are severely nephrotoxic. We proposed that the nephrotoxic ity of cisplatin was dependent on the cleavage of a cisplatin-glutathi one conjugate by GGT. To test this hypothesis, renal GGT activity was blocked in male Sprague-Dawley rats by acivicin, a non-competitive inh ibitor of GGT. Treatment with cisplatin alone caused extensive acute n ecrosis of the proximal tubules, but the proximal tubule cells appeare d normal in rats treated with acivicin prior to cisplatin. Blood urea nitrogen and serum creatinine levels confirmed the protective effect o f acivicin. Glutathione is a physiological substrate for GGT. Administ ration of an 83-fold excess of glutathione 30 min prior to cisplatin a lso inhibited cisplatin-induced nephrotoxicity. These data provide imp ortant new evidence that a large bolus of glutathione blocks the nephr otoxicity of cisplatin by competitively inhibiting GGT. These results indicate that cisplatin is conjugated to glutathione in vivo. The plat inum-glutathione conjugate is nontoxic until metabolized by the proxim al tubule cells. Formation of the nephrotoxic derivative of cisplatin requires GGT activity.