Connexin32: a mediator of acetaminophen- induced liver injury?

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Maes, Michael ; McGill, Mitchell R. ; da Silva, Tereza Cristina ; Lebofsky, Margitta ; Monteiro de Araujo, Cintia Maria ; Tiburcio, Tayna ; Alves Pereira, Isabel Veloso ; Willebrords, Joost ; Yanguas, Sara Crespo ; Farhood, Anwar ; Zaidan Dagli, Maria Lucia ; Jaeschke, Hartmut ; Cogliati, Bruno ; Vinken, Mathieu

• Document type: Journal article
• Source: TOXICOLOGY MECHANISMS AND METHODS; v. 26, n. 2, p. 9-pg., 2016-02-12.

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. (AU)

• FAPESP's process: 13/50420-6 - Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease
• Grantee: Mathieu Frederick Alexander Vinken
• Support Opportunities: Research Projects - SPEC Program