Adenosine triphosphate (ATP) levels in paracetamol-induced cell injury in the rat in vivo and in vitro.
We have investigated the relationship between ATP levels and the onset and progression of cell injury induced by paracetamol overdose both in vivo and in vitro. Liver slices obtained from phenobarbitone-induced and non-induced rats were used in a model in vitro system. Slices were exposed to paracetamol (2-10 mM), for 120 min and then incubated without paracetamol for a further 240 min. ATP levels are reduced upon exposure to paracetamol in liver slices from both phenobarbitone-induced and non-induced rats. Cell injury, as quantified by measuring leakage of lactate dehydrogenase (LDH) and potassium (K+), does not become apparent until 240 min, some 120 min after exposure to paracetamol had ended. This irreversible cell injury is not observed in liver slices from non-induced rats. For in vivo studies rats were phenobarbitone-induced and received i.p. injections of 800 mg/kg body weight paracetamol. Hepatic ATP levels were measured and are found to drop sharply by 3 h post-injection. Development of irreversible hepatic cell injury was assessed by measuring serum enzyme (ALT) activity. ALT levels do not rise until 12 h have elapsed. Paracetamol in overdose gives rise to ATP depletion in liver cells, that is early, independent of paracetamol metabolism and probably spread throughout the lobule. In contrast cell injury is found late and only in our phenobarbitone-induced rats. No cell injury is observed in liver slices from non-induced rats. This suggests that while the level of ATP depletion which is observed may be a necessary part of cell injury by paracetamol, it is not a sufficient cause.
Martin
F L
FL
Department of Medicine, University College London, UK.
McLean
A E
AE
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000633:toxicity; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D011188:Potassium; D010634:Phenobarbital