title: Involvement of connexin43 in acetaminophen-induced liver injury.
abstract: 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.
  
  
  
  C57BL/6 mice were overdosed with 300mg/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.
  
  
  
  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.
  
  
  
  These results suggest that hepatic connexin43-based signaling may protect against acetaminophen-induced liver toxicity.
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Michaël
authors.initials: M
authors.lastname: Maes
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: McGill
authors.affiliation: Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Tereza Cristina
authors.initials: TC
authors.lastname: da Silva
authors.affiliation: Myeloid Cell Immunology Lab, VIB Inflammation Research Center, Ghent, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Chloé
authors.initials: C
authors.lastname: Abels
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States.
authors.forename: Margitta
authors.initials: M
authors.lastname: Lebofsky
authors.affiliation: Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Cintia
authors.initials: C
authors.lastname: Maria Monteiro de Araújo
authors.affiliation: Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Taynã
authors.initials: T
authors.lastname: Tiburcio
authors.affiliation: Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Isabel
authors.initials: I
authors.lastname: Veloso Alves Pereira
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Willebrords
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Crespo Yanguas
authors.affiliation: Department of Pathology, St. David's North Austin Medical Center, Austin, United States.
authors.forename: Anwar
authors.initials: A
authors.lastname: Farhood
authors.affiliation: Myeloid Cell Immunology Lab, VIB Inflammation Research Center, Ghent, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Beschin
authors.affiliation: Myeloid Cell Immunology Lab, VIB Inflammation Research Center, Ghent, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Jo A
authors.initials: JA
authors.lastname: Van Ginderachter
authors.affiliation: Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Zaidan Dagli
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, United States.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.affiliation: Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Bruno
authors.initials: B
authors.lastname: Cogliati
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium. Electronic address: mvinken@vub.ac.be.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vinken
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018031:Connexin 43 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D018712:Analgesics, Non-Narcotic; D018031:Connexin 43; D012333:RNA, Messenger; D000082:Acetaminophen
keywords: Acetaminophen; Acute liver injury; Connexin43; Hepatotoxicity