title: RETRACTED: Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity.
abstract: Full length keratin-18 (FL-K18) and High Mobility Group Box-1 (HMGB1) represent circulating indicators of necrosis during acetaminophen (APAP) hepatotoxicity in vivo. In addition, the caspase-cleaved fragment of K18 (cK18) and hyper-acetylated HMGB1 represent serum indicators of apoptosis and immune cell activation, respectively. The study aim was to assess their mechanistic utility to establish the balance between apoptosis, necrosis, and immune cell activation throughout the time course of clinical APAP hepatotoxicity.
  
  
  
  HMGB1 (total, acetylated) and K18 (apoptotic, necrotic) were identified and quantified by novel LC-MS/MS assays in APAP overdose patients (n=78).
  
  
  
  HMGB1 (total; 15.4±1.9ng/ml, p<0.01, acetylated; 5.4±2.6ng/ml, p<0.001), cK18 (5649.8±721.0U/L, p<0.01), and FL-K18 (54770.2±6717.0U/L, p<0.005) were elevated in the sera of APAP overdose patients with liver injury compared to overdose patients without liver injury and healthy volunteers. HMGB1 and FL-K18 correlated with alanine aminotransferase (ALT) activity (R(2)=0.60 and 0.58, respectively, p<0.0001) and prothrombin time (R(2)=0.62 and 0.71, respectively, p<0.0001). Increased total and acetylated HMGB1 and FL-K18 were associated with worse prognosis (King's College Criteria) or patients that died/required liver transplant compared to spontaneous survivors (all p<0.05-0.001), a finding not reflected by ALT and supported by ROC analysis. Acetylated HMGB1 was a better predictor of outcome than the other markers of cell death.
  
  
  
  K18 and HMGB1 represent blood-based tools to investigate the cell death balance clinical APAP hepatotoxicity. Activation of the immune response was seen later in the time course as shown by the distinct profile of acetylated HMGB1 and was associated with worse outcome.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK. Electronic address: d.antoine@liv.ac.uk.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Rosalind E
authors.initials: RE
authors.lastname: Jenkins
authors.affiliation: University/BHF Centre for Cardiovascular Science, Edinburgh University & NPIS Edinburgh, Scottish Poisons Information Bureau, Edinburgh, UK.
authors.forename: James W
authors.initials: JW
authors.lastname: Dear
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Williams
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: McGill
authors.affiliation: Department of Pulmonary and Critical Care Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sharpe
authors.affiliation: Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors.forename: Darren G
authors.initials: DG
authors.lastname: Craig
authors.affiliation: Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Simpson
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000175:diagnosis* / Q000473:pathology*; D005260:Female; D024243:HMGB1 Protein / Q000097:blood*; D006801:Humans; D053538:Keratin-18 / Q000097:blood*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D011379:Prognosis
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; D053538:Keratin-18; D000082:Acetaminophen; D000410:Alanine Transaminase