Protection in the late stages of paracetamol-induced liver cell injury with fructose, cyclosporin A and trifluoperazine

A fixed combination of the three components, fructose, cyclosporin A and trifluoperazine (FCAT), was found to protect in the late stage of paracetamol-induced liver cell injury both in vivo and in an in vivo/in vitro system. Rats pre-induced with phenobarbitone were given a paracetamol dose of 1 g/kg i.p. The combination of FCAT was given orally 3 h or 3 and 8 h after paracetamol and was able to afford protection as seen by measurement of plasma alanine transaminase (ALT) levels at 24 h. In the in vivo/in vitro system, rats pre-induced with phenobarbitone were dosed with paracetamol 1 g/kg i.p. to initiate injury and liver slices were then taken 3, 4 and 5 h later. The liver slices were then incubated for up to 18 h with the protective agents (FCAT) and the progression of injury followed. Injury was assessed by lactate dehydrogenase (LDH) leakage into the medium and potassium content of the slices. FCAT significantly reduced the injury even as assessed after 5 h in vivo initiation and 18 h progression in vitro. Mitochondrial membrane potential was also maintained in the FCAT-treated liver slices from paracetamol-treated rats as seen by the ability to maintain a gradient of triphenyl methyl phosphonium (TPMP(+)) between the cell and external medium. All three compounds are required for protection, indicating that more than one event is critical to the survival of the cell and each target point needs to be protected for effective long-term cell survival. The in vivo/in vitro system has been found to give a better comparability to the in vivo situation than injury models that take 6 h or less (Beales and McLean, 1995, in press).