The effect of Z‐FA.FMK on D ‐galactosamine/TNF‐α‐induced liver injury in mice

Cathepsin B is a cysteine proteinase, considered to have an important role in apoptosis, which is activated by D ‐galactosamine and tumor necrosis factor‐alpha ( D ‐GalN/TNF‐α). Benzyloxycarbonyl‐ L ‐phenylalanine fluoromethyl ketone (Z‐FA.FMK) is a cathepsin B inhibitor used in research on apoptotic pathways. The aim of this study was to investigate the role of Z‐FA.FMK on apoptotic cell death, cell proliferation and liver damage induced by a D ‐GalN/TNF‐α combination in mice. In the study, 1 h after administration of 8 mg/kg Z‐FA.FMK by intravenous injection, D ‐GalN (700 mg/kg) and TNF‐α (15 µg/kg) were administered by a single intraperitoneal injection. In the group given D ‐GalN/TNF‐α, the following results were found: Degenerative changes in the liver tissue, significant increase in the number of both TUNEL and activated caspase‐3‐positive hepatocytes, a decrease in the number of PCNA‐positive hepatocytes, an increase in lipid peroxidation (LPO) levels and a decrease in glutathione (GSH) and DNA levels in the liver tissue. In contrast, in the group given D ‐GalN/TNF‐α and Z‐FA.FMK, a decrease in the damage of the liver tissue, a significant decrease in TUNEL and activated caspase‐3‐positive hepatocytes, a significant increase in the number of PCNA‐positive hepatocytes, a decrease in the LPO levels, an increase in GSH and DNA levels in the liver tissue were found. As a result, microscopic and biochemical evaluations indicate that Z‐FA.FMK plays a protective role against liver injury induced by D ‐GalN/TNF‐α and it has an inverse effect on hepatocyte apoptosis and proliferation in BALB/c mice. Copyright © 2006 John Wiley & Sons, Ltd.