title: 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.
authors.affiliation: a Department of In Vitro Toxicology and Dermato-Cosmetology , Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel , Brussels , Belgium .
authors.forename: Michaël
authors.initials: M
authors.lastname: Maes
authors.affiliation: b Department of Pharmacology , Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City , KS , USA .
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: McGill
authors.affiliation: c Department of Pathology , School of Veterinary Medicine and Animal Science, University of São Paulo , São Paulo , Brazil , and.
authors.forename: Tereza Cristina
authors.initials: TC
authors.lastname: da Silva
authors.affiliation: b Department of Pharmacology , Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City , KS , USA .
authors.forename: Margitta
authors.initials: M
authors.lastname: Lebofsky
authors.affiliation: c Department of Pathology , School of Veterinary Medicine and Animal Science, University of São Paulo , São Paulo , Brazil , and.
authors.forename: Cintia
authors.initials: C
authors.lastname: Maria Monteiro de Araújo
authors.affiliation: c Department of Pathology , School of Veterinary Medicine and Animal Science, University of São Paulo , São Paulo , Brazil , and.
authors.forename: Taynã
authors.initials: T
authors.lastname: Tiburcio
authors.affiliation: c Department of Pathology , School of Veterinary Medicine and Animal Science, University of São Paulo , São Paulo , Brazil , and.
authors.forename: Isabel
authors.initials: I
authors.lastname: Veloso Alves Pereira
authors.affiliation: a Department of In Vitro Toxicology and Dermato-Cosmetology , Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel , Brussels , Belgium .
authors.forename: Joost
authors.initials: J
authors.lastname: Willebrords
authors.affiliation: a Department of In Vitro Toxicology and Dermato-Cosmetology , Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel , Brussels , Belgium .
authors.forename: Sara
authors.initials: S
authors.lastname: Crespo Yanguas
authors.affiliation: d Department of Pathology , St. David's North Austin Medical Center , Austin , TX , USA.
authors.forename: Anwar
authors.initials: A
authors.lastname: Farhood
authors.affiliation: c Department of Pathology , School of Veterinary Medicine and Animal Science, University of São Paulo , São Paulo , Brazil , and.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Zaidan Dagli
authors.affiliation: b Department of Pharmacology , Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City , KS , USA .
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.affiliation: c Department of Pathology , School of Veterinary Medicine and Animal Science, University of São Paulo , São Paulo , Brazil , and.
authors.forename: Bruno
authors.initials: B
authors.lastname: Cogliati
authors.affiliation: a Department of In Vitro Toxicology and Dermato-Cosmetology , Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel , Brussels , Belgium .
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vinken
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D019803:Glutathione Disulfide / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011485:Protein Binding; D000097002:Gap Junction beta-1 Protein
chemical_list: D000082:Acetaminophen; D000410:Alanine Transaminase; D017630:Connexins; D016207:Cytokines; D019803:Glutathione Disulfide; D018809:Proliferating Cell Nuclear Antigen; D000097002:Gap Junction beta-1 Protein
keywords: Acetaminophen; connexin32; gap junction; hepatotoxicity