Sadzuka Y, Shimizu Y, Takino Y, Hirota S
School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Biochem Pharmacol. 1994 Aug 3;48(3):453-9. doi: 10.1016/0006-2952(94)90274-7.
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.
为了降低顺铂诱导的肾毒性，将谷胱甘肽S-转移酶（GST）诱导剂和一种GST抑制剂与顺铂联合应用于大鼠。反式氧化二苯乙烯（t-SO）和丙硫氧嘧啶（PTU）为GST诱导剂，酮洛芬为GST抑制剂。这些GST诱导剂和抑制剂与顺铂的联合应用降低了顺铂诱导的肾毒性。与顺铂联合使用的药物组合抑制了顺铂诱导的尿中总GST活性增加。与仅使用顺铂的组相比，t-SO与顺铂的组合增加了肾脏中的总GST活性。t-SO组合将单独使用顺铂诱导的GST-α活性降低恢复到对照水平。然而，与单独使用顺铂诱导的降低相比，t-SO组合后的谷胱甘肽过氧化物酶（GSHpx）活性进一步降低。与单独使用顺铂的组相比，PTU与顺铂的组合增加了总GST、GST-α和GSHpx活性。然而，PTU严重降低了谷胱甘肽（GSH）水平。酮洛芬与顺铂的组合使GST-μ和-α活性正常化，并提高了顺铂诱导的GSHpx活性降低和GSH水平。这些发现表明酮洛芬降低了顺铂诱导的肾毒性。
