COMPARISON OF PARACETAMOL-INDUCED HEPATOTOXICITY IN THE RAT IN-VIVO WITH PROGRESSION OF CELL INJURY IN-VITRO IN RAT-LIVER SLICES

The flux in rat hepatic ratio of adenosine triphosphate levels to aden osine diphosphate levels (ATP/ADP) during the onset and progression of paracetamol-induced cell injury both in vivo and in vitro were invest igated and compared. Leakage of lactate dehydrogenase (LDH) and potass ium (Kt), and mg water/mg dry weight quantified cell injury. ATP and A DP levels were determined using the luciferin-luciferase bioluminescen ce assay. For in vitro studies, liver slices obtained from phenobarbit one-induced rats were exposed to 10 mM paracetamol for 120 min (T-0-T- 120) and, then incubated without paracetamol up to a further 240 min ( T-120-T-360) For in vivo studies groups of four phenobarbitone-induced rats received i.p. injections of 800 mg/kg paracetamol. ATP/ADP ratio s fall upon exposure to paracetamol both in vitro and in vivo. However , unlike the in vitro situation where the fall in ATP/ADP ratios prece des and accompanies the progression of cell injury, the in vivo fall i n ATP/ADP ratios is shown to occur as cell injury measurements begin t o recover to control levels. However, despite these differences classi c paracetamol-induced centrilobular necrosis is observed to occur both in vitro and in vivo. This study demonstrates that the liver slice mo del is a simple and useful technique to investigate the underlying mec hanisms of paracetamol-induced cell injury.