REEVALUATION OF CYCLOSPORINE-INDUCED HEPATOTOXICITY IN THE ISOLATED-PERFUSED RAT-LIVER

Livers of male rats were perfused for 120 min in a recirculating hemog lobin-free system with different concentrations of cyclosporine (CS 2, 10, 50, 150 and 200 mg/l). CS produced damage to the livers in a dose dependent manner. The first sign of hepatotoxicity was a reduction of bile flow amounting to 50% already at 50 mg/l CS. At concentrations o f 150 mg/l and 200 mg/l, CS lead to a nearly complete suppression of b ile flow, furthermore to a release of cytosolic (GPT, glutamate-pyruva te transaminase, LDH, lactate dehydrogenase) and mitochondrial (GLDH, glutamate dehydrogenase) enzymes into the perfusate and to a decrease in hepatic oxygen consumption (30% at 200 mg/l CS). As a consequence o f the reduced aerobic energy supply, hepatic ATP concentration decline d (70% at 200 mg/l CS). The hepatic concentrations of reduced glutathi one (GSH) were not changed but those of oxidized glutathione (GSSG) in creased up to 5-fold by CS. Malondialdehyde (MDA) concentrations in th e liver and in the perfusate were not affected consistently by CS. The toxic actions of CS in the isolated rat liver were not influenced (a) by the feeding status of the rats (fed or fasted before surgery) or ( b) by addition of superoxide dismutase (SOD, 20 mg/l) and catalase (20 mg/l) to the perfusate 30 min before CS. On the other hand, CS-induce d hepatic injury could be attenuated or inhibited completely by additi on to the perfusate of (1) 2 mmol/l GSH; (2) 12 mmol/l serine; (3) 12 mmol/l glycine; (4) 0.09 mmol/l deferoxamine (DFO). Conclusions: CS in duces cholestasis at lower concentrations, probably by another mechani sm(s) than the other signs of hepatotoxicity (enzyme release, ATP depl etion). Several lines of evidence indicate a probable participation of reactive oxygen species in CS-induced hepatotoxicity. GSH, DFO, glyci ne and serine could provide therapeutic opportunities to prevent CS-in duced hepatotoxicity in patients treated with high doses of CS. (C) 19 97 Elsevier Science Ireland Ltd.