Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity

Author(s):Show less -

Maes, Michael ; McGill, Mitchell R. ; da Silva, Tereza Cristina ; Abels, Chloe ; Lebofsky, Margitta ; Weemhoff, James L. ; Tiburcio, Tayna ; Alves Pereira, Isabel Veloso ; Willebrords, Joost ; Yanguas, Sara Crespo ; Farhood, Anwar ; Beschin, Alain ; Van Ginderachter, Jo A. ; Penuela, Silvia ; Jaeschke, Hartmut ; Cogliati, Bruno ; Vinken, Mathieu

• Document type: Journal article
• Source: ARCHIVES OF TOXICOLOGY; v. 91, n. 5, p. 2245-2261, MAY 2017.
• Web of Science Citations: 8

Abstract

Pannexins constitute a relatively new family of transmembrane proteins that form channels linking the cytoplasmic compartment with the extracellular environment. The presence of pannexin1 in the liver has been documented previously, where it underlies inflammatory responses, such as those occurring upon ischemia-reperfusion injury. In the present study, we investigated whether pannexin1 plays a role in acute drug-induced liver toxicity. Hepatic expression of pannexin1 was characterized in a mouse model of acetaminophen-induced hepatotoxicity. Subsequently, mice were overdosed with acetaminophen followed by treatment with the pannexin1 channel inhibitor (10)Panx1. Sampling was performed 1, 3, 6, 24 and 48 h after acetaminophen administration. Evaluation of the effects of pannexin1 channel inhibition was based on a number of clinically relevant readouts, including protein adduct formation, measurement of aminotransferase activity and histopathological examination of liver tissue as well as on a series of markers of inflammation, oxidative stress and regeneration. Although no significant differences were found in histopathological analysis, pannexin1 channel inhibition reduced serum levels of alanine and aspartate aminotransferase. This was paralleled by a reduced amount of neutrophils recruited to the liver. Furthermore, alterations in the oxidized status were noticed with upregulation of glutathione levels upon suppression of pannexin1 channel opening. Concomitant promotion of regenerative activity was detected as judged on increased proliferating cell nuclear antigen protein quantities in 10Panx1-treated mice. Pannexin1 channels are important actors in liver injury triggered by acetaminophen. Inhibition of pannexin1 channel opening could represent a novel approach for the treatment of drug-induced 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