Immediate rise in intracellular calcium and glycogen phosphorylase a activities upon acetaminophen covalent binding leading to hepatotoxicity in mice.
Drugs and chemicals that cause irreversible damage to cells may do so by producing specific defects in calcium regulation. The present studies examined glycogen phosphorylase as an index for assessing in vivo changes leading to excessive calcium ion activity, a putative pathogen, during the course of acetaminophen-induced liver injury. Administration of 500 mg/kg acetaminophen per os to mice depleted hepatic glutathione to a nadir by 1 h. Covalent binding to hepatocellular macromolecules commenced at this time and then rose out of the non-injurious background range at 1.5 h, coincident with a sharp rise in phosphorylase a activity. Phosphorylase activation preceded the leakage of alanine aminotransferase into plasma by several hours but appeared only after glutathione was depleted in excess of 80%. During the first 3 h, phosphorylase a activity rose in direct proportion to the amount of acetaminophen covalent binding. Glutathione depletion alone was not responsible for phosphorylase activation because the glutathione biosynthesis inhibitor, D,L-buthionine sulfoximine, produced comparable glutathione depletion but failed to stimulate phosphorylase activity or produce cell injury. Because phosphorylase a activity is thought to mirror changes in Ca2+ activity in vivo, these results support the hypothesis that acetaminophen-induced hepatocellular injury is related to the impairment of Ca2+ regulation.
Corcoran
G B
GB
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Bauer
J A
JA
Lau
T W
TW
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D019328:Buthionine Sulfoximine; D002118:Calcium / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D010762:Phosphorylase a / Q000378:metabolism*; D006005:Phosphorylases / Q000378:metabolism*; D011485:Protein Binding
D008717:Methionine Sulfoximine; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; D010762:Phosphorylase a; D006005:Phosphorylases; D005978:Glutathione; D002118:Calcium