Protection against cisplatin-induced nephrotoxicity in the rat by inducers and an inhibitor of glutathione S-transferase.

In an attempt to decrease cisplatin-induced nephrotoxicity, glutathione S-transferase (GST) inducers and a GST inhibitor were combined with cisplatin and administered to rats. t-Stilbene oxide (t-SO) and propylthiouracil (PTU) were the GST inducers, and ketoprofen was the GST inhibitor. Combinations of these GST inducers and the inhibitor with cisplatin decreased cisplatin-induced nephrotoxicity. The drug combinations with cisplatin inhibited the cisplatin-induced increase in urinary total GST activity. The combination of t-SO with cisplatin increased total GST activity in the kidney, compared to levels in the cisplatin only group. The t-SO combination recovered the cisplatin alone-induced decrease in GST-alpha activity to control levels. However, glutathione peroxidase (GSHpx) activity after the t-SO combination was ever further reduced compared to the cisplatin alone-induced decrease. The combination of PTU, with cisplatin increased total GST, GST-alpha and GSHpx activity, compared to the cisplatin alone group. However, PTU severely decreased the glutathione (GSH) level. The combination of ketoprofen with cisplatin normalized GST-mu and -alpha activity, and elevated the cisplatin-induced decrease of GSHpx activity and GSH. These findings suggest that ketoprofen decreases cisplatin-induced nephrotoxicity.