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Involvement of connexin43 in acetaminophen-induced liver injury

Michaël Maes1, Mitchell R McGill2, Tereza Cristina da Silva3

  • 1Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.

Biochimica Et Biophysica Acta
|February 26, 2016
PubMed
Abstract

Insights

Acetaminophen (APAP) overdose impairs liver gap junction communication. Connexin43 upregulation in hepatocytes appears protective against APAP-induced liver injury, suggesting a therapeutic target.

Area of Science:

  • Hepatology
  • Toxicology
  • Cellular Biology

Background:

  • Gap junctions are crucial for liver homeostasis but their role in drug-induced liver injury (DILI) is complex.
  • Gap junctions can be both targets and mediators of liver toxicity, especially from acetaminophen (APAP).

Purpose of the Study:

  • Investigate the role of connexins (Cx26, Cx32, Cx43) in APAP-induced hepatotoxicity.
  • Determine the protective potential of connexin43 (Cx43) in APAP-induced liver injury.

Main Methods:

  • Mice received a toxic dose of APAP; connexin expression, localization, and gap junction function were analyzed.
  • APAP-induced liver injury was compared between wild-type and Cx43-deficient mice.
  • Toxicological parameters included protein adducts, ALT activity, cytokines, and glutathione levels.

Main Results:

  • APAP intoxication disrupted gap junction communication and altered connexin expression from Cx32/Cx26 to Cx43.
  • Hepatocytes produced increased Cx43, suggesting a protective response.
  • Cx43-deficient mice exhibited exacerbated liver cell death, inflammation, and oxidative stress.

Conclusions:

  • Hepatic Cx43-based signaling plays a protective role against APAP-induced liver toxicity.
  • Targeting Cx43 may offer a therapeutic strategy for managing acetaminophen overdose.
Keywords:
AcetaminophenAcute liver injuryConnexin43Hepatotoxicity

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