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.
Sadzuka
Y
Y
School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Shimizu
Y
Y
Takino
Y
Y
Hirota
S
S
D000818:Animals; D002945:Cisplatin / Q000633:toxicity*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000302:isolation & purification; D007527:Isoenzymes / Q000302:isolation & purification; D007660:Ketoprofen / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010984:Platinum / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D007527:Isoenzymes; D010984:Platinum; D007660:Ketoprofen; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D002945:Cisplatin