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Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen
D L Laskin1, C R Gardner, V F Price
1Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08855-0789, USA.
Abstract:
Acetaminophen is a mild analgesic and antipyretic agent that is safe and effective when taken in therapeutic doses. Ingestion of overdoses, however, may lead to acute liver failure accompanied by centrilobular degeneration and necrosis. Although the toxicity of acetaminophen is generally thought to be caused by direct interaction of its reactive metabolites with cellular macromolecules, recent studies have suggested that nonparenchymal cells also may contribute to tissue injury indirectly through the release of cytotoxic mediators. We analyzed the potential role of hepatic macrophages in acetaminophen hepatotoxicity by examining the effects of modulating the activity of these cells on tissue injury. Treatment of male Long Evans Hooded rats with acetaminophen (800 mg/kg) was found to induce extensive centrilobular hepatic necrosis. Pretreatment of the rats with either dextran sulfate or gadolinium chloride, two inhibitors of hepatic macrophage functioning, completely blocked hepatic necrosis, as well as increases in serum transaminase levels induced by acetaminophen. Interestingly, treatment of rats with the macrophage activator, lipopolysaccharide (LPS), also reduced tissue injury induced by acetaminophen. To exclude the possibility that the effects of gadolinium chloride, dextran sulfate, or LPS were due to alterations in acetaminophen metabolism, we analyzed the effects of these agents on various pharmacokinetic properties of this analgesic. Dextran sulfate and gadolinium chloride had no effect on the half-life of a low dose of acetaminophen (20 mg/kg), or on the activity of any of its individual pathways of metabolism, including the formation of acetaminophen-mercapturic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Hepatic macrophages play a crucial role in acetaminophen-induced liver injury. Inhibiting or activating these cells significantly altered the severity of liver damage in rats, suggesting a therapeutic target for acetaminophen overdose.
Area of Science:
- Hepatology
- Immunology
- Toxicology
Background:
- Acetaminophen (APAP) overdose causes acute liver failure.
- APAP toxicity is linked to reactive metabolites and potentially nonparenchymal cells.
- The role of hepatic macrophages in APAP hepatotoxicity requires further investigation.
Purpose of the Study:
- To investigate the role of hepatic macrophages in acetaminophen-induced liver injury.
- To determine if modulating macrophage activity affects acetaminophen hepatotoxicity.
Main Methods:
- Rats were treated with acetaminophen (800 mg/kg) to induce liver injury.
- Macrophage function was inhibited using dextran sulfate or gadolinium chloride.
- Macrophage activity was modulated using lipopolysaccharide (LPS).
- Acetaminophen metabolism and pharmacokinetics were analyzed.
Main Results:
- Acetaminophen induced centrilobular hepatic necrosis and elevated serum transaminases.
- Inhibiting hepatic macrophages with dextran sulfate or gadolinium chloride completely blocked liver injury.
- Activating macrophages with LPS also reduced acetaminophen-induced tissue damage.
- These agents did not alter acetaminophen metabolism or pharmacokinetics.
Conclusions:
- Hepatic macrophages are critical mediators of acetaminophen-induced liver injury.
- Modulating hepatic macrophage activity offers a potential therapeutic strategy for acetaminophen overdose.
- Targeting macrophages may mitigate acetaminophen hepatotoxicity independently of altering drug metabolism.