title: Combination of tauroursodeoxycholic acid and N-acetylcysteine exceeds standard treatment for acetaminophen intoxication.
abstract: Acetaminophen overdose in mice is characterized by hepatocyte endoplasmic reticulum stress, which activates the unfolded protein response, and centrilobular hepatocyte death. We aimed at investigating the therapeutic potential of tauroursodeoxycholic acid, a hydrophilic bile acid known to have anti-apoptotic and endoplasmic reticulum stress-reducing capacities, in experimental acute liver injury induced by acetaminophen overdose.
  
  
  
  Mice were injected with 300 mg/kg acetaminophen, 2 hours prior to receiving tauroursodeoxycholic acid, N-acetylcysteine or a combination therapy, and were euthanized 24 hours later. Liver damage was assessed by serum transaminases, liver histology, terminal deoxynucleotidyl transferase dUTP nick end labelling staining, expression profiling of inflammatory, oxidative stress, unfolded protein response, apoptotic and pyroptotic markers.
  
  
  
  Acetaminophen overdose resulted in a significant increase in serum transaminases, hepatocyte cell death, unfolded protein response activation, oxidative stress, NLRP3 inflammasome activation, caspase 1 and pro-inflammatory cytokine expressions. Standard of care, N-acetylcysteine and, to a lesser extent, tauroursodeoxycholic treatment were associated with significantly lower transaminase levels, hepatocyte death, unfolded protein response activation, oxidative stress markers, caspase 1 expression and NLRP3 levels. Importantly, the combination of N-acetylcysteine and tauroursodeoxycholic acid improved serum transaminase levels, reduced histopathological liver damage, UPR-activated CHOP, oxidative stress, caspase 1 expression, NLRP3 levels, IL-1β levels and the expression of pro-inflammatory cytokines and this to a greater extend than N-acetylcysteine alone.
  
  
  
  These findings indicate that a combination strategy of N-acetylcysteine and tauroursodeoxycholic acid surpasses the standard of care in acetaminophen-induced liver injury in mice and might represent an attractive therapeutic opportunity for acetaminophen-intoxicated patients.
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Paridaens
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Raevens
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Colle
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Eliene
authors.initials: E
authors.lastname: Bogaerts
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Yves-Paul
authors.identifier: 0000-0002-7829-6732
authors.initials: YP
authors.lastname: Vandewynckel
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Verhelst
authors.affiliation: Department of Pathology, Ghent University, Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Hoorens
authors.affiliation: Liver Cell Biology Lab, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Leo A
authors.initials: LA
authors.lastname: van Grunsven
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Anja
authors.initials: A
authors.lastname: Geerts
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Devisscher
mesh_terms: D000082:Acetaminophen / Q000506:poisoning*; D000111:Acetylcysteine / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D016207:Cytokines; D000082:Acetaminophen; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D000410:Alanine Transaminase; D000111:Acetylcysteine
keywords: endoplasmic reticulum stress; hepatotoxicity; paracetamol; tauroursodeoxycholic acid