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Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity

Herbert C Yohe1, Kimberley A O'Hara, Jane A Hunt

  • 1Veterans Administration Medical Center, White River Junction, VT 05009, USA. herbert.c.yohe@dartmouth.edu

American Journal of Physiology. Gastrointestinal and Liver Physiology
|January 28, 2006
PubMed

Insights

Toll-like receptor 4 (TLR4) plays a role in alcohol-exacerbated acetaminophen (APAP) liver injury. Mice with functional TLR4 showed increased APAP toxicity after alcohol pretreatment, unlike mice with mutated TLR4.

Area of Science:

  • Hepatology
  • Immunology
  • Toxicology

Background:

  • Acetaminophen (APAP) overdose is a leading cause of acute liver failure.
  • Alcohol consumption is a common factor in APAP overdose cases.
  • Toll-like receptor 4 (TLR4) mediates inflammatory responses to endotoxins and may influence drug-induced liver injury.

Purpose of the Study:

  • To investigate the role of Toll-like receptor 4 (TLR4) in alcohol-mediated acetaminophen (APAP) hepatotoxicity.
  • To compare APAP-induced liver injury in endotoxin-responsive and endotoxin-insensitive mouse models following alcohol pretreatment.

Main Methods:

  • Mice with functional TLR4 (C3H/HeN) and mutated TLR4 (C3H/HeJ) were pretreated with ethanol and isopentanol for one week.
  • Subsequent administration of acetaminophen (APAP) was performed.
  • Liver damage, nitrotyrosine levels, and plasma TNF-alpha were assessed.
  • Portal blood endotoxin levels were measured.

Main Results:

  • Alcohol pretreatment alone did not cause liver damage but increased nitrotyrosine in C3H/HeN mice.
  • APAP treatment alone caused liver injury (steatosis, congestion, necrosis) in both mouse strains, more severe in C3H/HeN mice.
  • Alcohol pretreatment exacerbated APAP hepatotoxicity in C3H/HeN mice, increasing liver damage and TNF-alpha levels.
  • Alcohol pretreatment did not significantly increase APAP hepatotoxicity in C3H/HeJ mice.
  • Portal endotoxin levels remained low and were not affected by treatments.

Conclusions:

  • Toll-like receptor 4 (TLR4) signaling is implicated in the potentiation of acetaminophen hepatotoxicity by alcohol.
  • Targeting TLR4 may offer a therapeutic strategy for managing alcohol-associated APAP overdose.

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