Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity.
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 inhibitor10Panx1. 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 in10Panx1-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.
Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
Michaël
M
Maes
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Mitchell R
MR
McGill
Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
Tereza Cristina
TC
da Silva
Myeloid Cell Immunology Lab, VIB Inflammation Research Center, Ghent, Belgium.|Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
Chloé
C
Abels
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
Margitta
M
Lebofsky
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
James L
JL
Weemhoff
Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
Taynã
T
Tiburcio
Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
Isabel
I
Veloso Alves Pereira
Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
Joost
J
Willebrords
Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
Sara
S
Crespo Yanguas
Department of Pathology, St. David's North Austin Medical Center, Austin, TX, USA.
Anwar
A
Farhood
Myeloid Cell Immunology Lab, VIB Inflammation Research Center, Ghent, Belgium.|Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
Alain
A
Beschin
Myeloid Cell Immunology Lab, VIB Inflammation Research Center, Ghent, Belgium.|Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
Jo A
JA
Van Ginderachter
Department of Anatomy and Cell Biology, University of Western Ontario, London, Canada.
Silvia
S
Penuela
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
Hartmut
H
Jaeschke
Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
Bruno
B
Cogliati
Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium. mvinken@vub.ac.be.
Mathieu
M
Vinken
D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D017630:Connexins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D062787:Drug Overdose / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects
D017630:Connexins; D016207:Cytokines; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D000082:Acetaminophen
Acetaminophen; Cell death; Hepatotoxicity; Inflammation; Neutrophil; Pannexin