title: Comparison of paracetamol-induced hepatotoxicity in the rat in vivo with progression of cell injury in vitro in rat liver slices.
abstract: The flux in rat hepatic ratio of adenosine triphosphate levels to adenosine diphosphate levels (ATP/ADP) during the onset and progression of paracetamol-induced cell injury both in vivo and in vitro were investigated and compared. Leakage of lactate dehydrogenase (LDH) and potassium (K+), and mg water/mg dry weight quantified cell injury. ATP and ADP levels were determined using the luciferin-luciferase bioluminescence assay. For in vitro studies, liver slices obtained from phenobarbitone-induced rats were exposed to 10 mM paracetamol for 120 min (T0-T120) and, then incubated without paracetamol up to a further 240 min (T120-T360). For in vivo studies, groups of four phenobarbitone-induced rats received i.p. injections of 800 mg/kg paracetamol. ATP/ADP ratios fall upon exposure to paracetamol both in vitro and in vivo. However, unlike the in vitro situation where the fall in ATP/ADP ratios precedes and accompanies the progression of cell injury, the in vivo fall in ATP/ADP ratios is shown to occur as cell injury measurements begin to recover to control levels. However, despite these differences classic paracetamol-induced centrilobular necrosis is observed to occur both in vitro and in vivo. This study demonstrates that the liver slice model is a simple and useful technique to investigate the underlying mechanisms of paracetamol-induced cell injury.
authors.affiliation: Department of Medicine, University College London, UK.
authors.forename: F L
authors.initials: FL
authors.lastname: Martin
authors.forename: A E
authors.initials: AE
authors.lastname: McLean
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008954:Models, Biological; D009336:Necrosis; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D014810:Vitamin E; D000082:Acetaminophen; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; D007770:L-Lactate Dehydrogenase; D010634:Phenobarbital