Effect of acetaminophen hepatotoxicity on hepatic mitochondrial and microsomal calcium contents in mice.
The effect of toxic doses of acetaminophen on hepatic intracellular calcium compartmentation were studied in mice. No effects on the calcium contents of the mitochondria, microsomes or cytosol were observed 4 h after the administration of 175 and 375 mg/kg acetaminophen when compared to saline-treated controls. However, doses of 500 and 750 mg/kg of acetaminophen increased mitochondrial calcium contents at this time. Also, the 750 mg/kg dose caused marked alterations in the calcium contents of microsomal and cytosolic compartments. The time-course of the onset of these effects was examined using a 500 mg/kg dose. No changes in either mitochondrial, microsomal or cytosolic calcium contents were observed in the livers of mice treated with acetaminophen compared to saline-treated controls at either 1 or 2 h after dose administration. However, at 3, 4 and 24 h after acetaminophen, mitochondrial and cytosolic calcium contents were significantly increased above control values. The increases in mitochondrial and cytosolic calcium contents observed in the acetaminophen-intoxicated mouse liver appear to occur at the same time as the appearance of plasma membrane damage, as measured by sorbitol dehydrogenase leakage. The data suggest that a perturbation in hepatic calcium compartmentation is not an early event in acetaminophen-induced hepatotoxicity in the mouse.
Burcham
P C
PC
Department of Pharmacology, Queen Elizabeth II Medical Centre, University of Western Australia, Nedlands.
Harman
A W
AW
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002251:Carbon Tetrachloride / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism
D000082:Acetaminophen; D002251:Carbon Tetrachloride; D007064:L-Iditol 2-Dehydrogenase; D002118:Calcium