Related Experiment Videos
Effect of acetaminophen hepatotoxicity on hepatic mitochondrial and microsomal calcium contents in mice
1Department of Pharmacology, Queen Elizabeth II Medical Centre, University of Western Australia, Nedlands.
Abstract:
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.
Insights
Toxic doses of acetaminophen disrupt hepatic calcium balance in mice. Mitochondrial and cytosolic calcium levels increase significantly after acetaminophen overdose, but this is not an early sign of liver damage.
Area of Science:
- Hepatotoxicity
- Cellular Biology
- Toxicology
Background:
- Acetaminophen overdose is a leading cause of acute liver failure.
- Intracellular calcium dysregulation is implicated in various forms of cell injury.
- The role of hepatic calcium compartmentation in acetaminophen-induced liver injury requires further elucidation.
Purpose of the Study:
- To investigate the effects of toxic acetaminophen doses on hepatic intracellular calcium levels in mice.
- To determine the time-course of alterations in mitochondrial, microsomal, and cytosolic calcium content following acetaminophen administration.
Main Methods:
- Mice were administered varying doses of acetaminophen (175-750 mg/kg) or saline.
- Hepatic calcium content in mitochondria, microsomes, and cytosol was measured at different time points (1-24 hours).
- Plasma membrane damage was assessed by measuring sorbitol dehydrogenase (SDH) leakage.
Main Results:
- Doses of 500 and 750 mg/kg acetaminophen increased mitochondrial calcium content at 4 hours.
- The 750 mg/kg dose also altered microsomal and cytosolic calcium content.
- Significant increases in mitochondrial and cytosolic calcium were observed at 3, 4, and 24 hours post-acetaminophen (500 mg/kg), coinciding with SDH leakage.
Conclusions:
- Hepatic intracellular calcium compartmentation is altered by toxic acetaminophen doses in mice.
- The observed changes in calcium levels occur concurrently with plasma membrane damage, suggesting they are not an initial event.
- Perturbation of hepatic calcium is likely a later consequence, not an early trigger, of acetaminophen-induced hepatotoxicity.