Effects of inhibitors of phospholipase A2, cyclooxygenase and thromboxane synthetase on paracetamol hepatotoxicity in the rat.
This paper describes work on a proposed hypothesis of cell injury and death in which an hepatotoxin-induced rise in cytosolic free Ca2+ concentration activates phospholipase A2 (PLA2) resulting in the release of arachidonic acid (A.A.) from membrane phospholipids. A.A. is then converted to eicosanoids which are known to be formed during chemical cell injury. A rise in cytosolic free Ca2+ level (indicated by increased glycogen phosphorylase "a" activity) occurs about 12 h after paracetamol administration to rats. Inhibitors of PLA2, cyclooxygenase and thromboxane synthetase injected i.p. 7 h after paracetamol prevented hepatotoxicity as measured by SGPT activity but did not prevent an increase in glycogen phosphorylase "a" activity. Serum 11-deoxy-13,14-dihydro-15-keto-11 beta, 16 epsilon-cyclo prostaglandin E2 and thromboxane B2 measured by radioimmunoassay increased substantially soon after the increase in glycogen phosphorylase "a" activity. The data presented support the proposed sequence of events in which A.A., released from membrane phospholipids by Ca2(+)-activated PLA2, acts as substrate for the synthesis of cytodestructive eicosanoids.
Horton
A A
AA
School of Biochemistry, University of Birmingham, United Kingdom.
Wood
J M
JM
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids / Q000502:physiology*; D008297:Male; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D010762:Phosphorylase a / Q000378:metabolism; D051381:Rats; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D000082:Acetaminophen; D010762:Phosphorylase a; D000410:Alanine Transaminase; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D013930:Thromboxane-A Synthase; D002118:Calcium