Title

Involvement of connexin43 in acetaminophen-induced liver injury

Document Type

Journal Article

Publication Date

6-1-2016

Journal

Biochimica et Biophysica Acta - Molecular Basis of Disease

Volume

1862

Issue

6

DOI

10.1016/j.bbadis.2016.02.007

Keywords

Acetaminophen; Acute liver injury; Connexin43; Hepatotoxicity

Abstract

© 2016 Elsevier B.V. Background and aims: Being goalkeepers of liver homeostasis, gap junctions are also involved in hepatotoxicity. However, their role in this process is ambiguous, as gap junctions can act as both targets and effectors of liver toxicity. This particularly holds true for drug-induced liver insults. In the present study, the involvement of connexin26, connexin32 and connexin43, the building blocks of liver gap junctions, was investigated in acetaminophen-induced hepatotoxicity. Methods: C57BL/6 mice were overdosed with 300 mg/kg body weight acetaminophen followed by analysis of the expression and localization of connexins as well as monitoring of hepatic gap junction functionality. Furthermore, acetaminophen-induced liver injury was compared between mice genetically deficient in connexin43 and wild type littermates. Evaluation of the toxicological response was based on a set of clinically relevant parameters, including protein adduct formation, measurement of alanine aminotransferase activity, cytokines and glutathione. Results: It was found that gap junction communication deteriorates upon acetaminophen intoxication in wild type mice, which is associated with a switch in mRNA and protein production from connexin32 and connexin26 to connexin43. The upregulation of connexin43 expression is due, at least in part, to de novo production by hepatocytes. Connexin43-deficient animals tended to show increased liver cell death, inflammation and oxidative stress in comparison with wild type counterparts. Conclusion: These results suggest that hepatic connexin43-based signaling may protect against acetaminophen-induced liver toxicity.

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