PROTECTIVE EFFECT OF ULINASTATIN ON CISPLATIN-INDUCED TOXICITY IN THE KIDNEY EPITHELIAL CELL LINE, LLC-PK1

Abstract

Ulinastatin has a protective effect against acute pancreatitis and drug-induced nephrotoxicity in vivo. The protective effect of ulinastatin was investigated on toxicities induced by various nephrotoxic drugs using LLC-PK1 kidney epithe lial cells as a model system. The effects of ulinastatin on drug-induced toxicity were evaluated by measuring lactate dehydrogenase (LDH) release from LLCPK1 cells and apical membrane enzyme activity in the cell homogenate after treating the cells with cisplatin, gentamicin, cyclosporin A, uranyl nitrate, or carboplatin in the presence or absence of ulinastatin. When LLC-PK1 cells were treated with cisplatin, the release of LDH into the culture medium was elevated in a time-dependent manner (0-5 days). In the presence of 12,000 U/mL ulinastatin, cisplatin-induced LDH release was reduced to almost the same level as in nontreated controls. Simultaneous determination of apical membrane enzyme activities (gamma-glutamyltransferase and alkaline phosphatase) in the cell homogenate revealed that cisplatin-induced damage in these enzymes was also attenuated by the presence of ulinastatin. On the other hand, ulinastatin did not attenuate gentamicin-, cyclosporin A-, or uranyl nitrate-induced cellular toxicity in LLC-PK1 cells. Furthermore, stimulation of LDH release by carboplatin treatment was completely prevented in the presence of 6000 U/mL ulinastatin. These results suggest that ulinastatin selectively protects against cisplatin- and carboplatin-induced cell toxicities and is a possible candidate for use as a protective agent against cisplatin- and carboplatin-induced nephrotoxicity in cancer chemotherapy.

Keywords: :

• Cisplatin, Kidney Epithelial Cells, Llc-PK, Nephrotoxicity, Uli1 Nastatin