Protective effect of ulinastatin on cisplatin-induced toxicity in the kidney epithelial cell line, LLC-PK1

Ulinastatin has a protective effect against acute pancreatitis and drug-ind uced nephrotoxicity in vivo. The protective effect of ulinastatin was inves tigated on toxicities induced by various nephrotoxic drugs using LLC-PK1 ki dney epithelial cells as a model system. The effects of ulinastatin on drug -induced toxicity were evaluated by measuring lactate dehydrogenase (LDH) r elease from LLC-PK1 cells and apical membrane enzyme activity in the cell h omogenate 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 t he culture medium was elevated in a time-dependent manner (0-5 clays). In t he presence of 12,000 U/mL ulinastatin, cisplatin-induced LDH release was r educed to almost the same level as in nontreated controls. Simultaneous det ermination of apical membrane enzyme activities (gamma-glutamyltransferase and alkaline phosphatase) in the cell homogenate revealed that cisplatin-in duced damage in these enzymes was also attenuated by the presence of ulinas tatin. On the other hand, ulinastatin did not attenuate gentamicin-, cyclos porin A-, or uranyl nitrate-induced cellular toxicity in LLC-PK1 cells. Fur thermore, stimulation of LDH release by carboplatin treatment was completel y prevented in the presence of 6000 U/mL ulinastatin. These results suggest that ulinastatin selectively protects against cisplatin- and carboplatin-i nduced cell toxicities and is a possible candidate for use as a protective agent against cisplatin- and carboplatin-induced nephrotoxicity in cancer c hemotherapy.