Connexin32: a mediator of acetaminophen-induced liver injury?

Abstract

Connexin32 is the building block of hepatocellular gap junctions, which control direct intercellular communication and thereby act as goalkeepers of liver homeostasis. This study was set up to investigate whether connexin32 is involved in hepatotoxicity induced by the analgesic and antipyretic drug acetaminophen. To this end, whole body connexin32 knock-out mice were overdosed with acetaminophen followed by sampling at different time points within a 24-h time frame. Evaluation was done based upon a series of clinically and mechanistically relevant read-outs, including protein adduct formation, histopathological examination, measurement of alanine aminotransferase activity, cytokine production, levels of reduced and oxidized glutathione and hepatic protein amounts of proliferating cell nuclear antigen. In essence, it was found that genetic ablation of connexin32 has no influence on several key events in acetaminophen-induced hepatotoxicity, including cell death, inflammation or oxidative stress, yet it does affect production of protein adducts as well as proliferating cell nuclear antigen steady-state protein levels. This outcome is not in line with previous studies, which are contradicting on their own, as both amplification and alleviation of this toxicological process by connexin32 have been described. This could question the suitability of the currently available models and tools to investigate the role of connexin32 in acetaminophen-triggered hepatotoxicity.

• Acetaminophen
• connexin32
• gap junction
• hepatotoxicity

Acknowledgements

The authors wish to thank Miss Tineke Vanhalewyn, Miss Dinja De Win, Miss Shirlei Meire da Silva and Mister José Alexandre Coelho Pimentel for their dedicated technical assistance.

Declaration of interest

The authors report no declarations of interest. This work was financially supported by grants from the Agency for Innovation by Science and Technology in Flanders (IWT), the European Research Council (ERC Starting Grant 335476), the Fund for Scientific Research-Flanders (FWO grants G009514N and G010214N), the University Hospital of the Vrije Universiteit Brussel-Belgium (“Willy Gepts Fonds” UZ-VUB), the US National Institutes of Health (R01 DK102142), the University of São Paulo-Brazil and the Foundation for Research Support of the State of São Paulo-Brazil (FAPESP SPEC grant 2013/50420-6).