title: Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts.
abstract: OBJECTIVE
  There is a demand for more sensitive, specific and predictive biomarkers for drug-induced liver injury (DILI) than the gold standard used today, alanine aminotransferase (ALT). The aim of this study was to qualify novel DILI biomarkers (keratin-18 markers M65/M30, microRNA-122, glutamate dehydrogenase and alpha-foetoprotein) in human DILI.
  
  
  METHODS
  Levels of the novel biomarkers were measured by enzyme-linked immunosorbent assay or real-time quantitative reverse-transcription PCR (qRT-PCR) in two human DILI cohorts: a human volunteer study with acetaminophen and a human immunodeficiency virus (HIV)/tuberculosis (TB) study.
  
  
  RESULTS
  In the acetaminophen study, serum M65 and microRNA-122 levels were significantly increased at an earlier time point than ALT. Furthermore, the maximal elevation of M65 and microRNA-122 exceeded the increase in ALT. In the HIV/TB study, all the analysed novel biomarkers increased after 1 week of treatment. In contrast to ALT, the novel biomarkers remained stable in a human cohort with exercise-induced muscular injury.
  
  
  CONCLUSIONS
  M65 and microRNA-122 are potential biomarkers of DILI superior to ALT with respect to sensitivity and specificity.
authors.affiliation: AstraZeneca R&D, Innovative Medicines Personalised Healthcare & Biomarkers, Science for Life Laboratory, Solna, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Thulin
authors.forename: Gunnar
authors.initials: G
authors.lastname: Nordahl
authors.forename: Marcus
authors.initials: M
authors.lastname: Gry
authors.forename: Getnet
authors.initials: G
authors.lastname: Yimer
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
authors.forename: Eyasu
authors.initials: E
authors.lastname: Makonnen
authors.forename: Getachew
authors.initials: G
authors.lastname: Aderaye
authors.forename: Lars
authors.initials: L
authors.lastname: Lindquist
authors.forename: C Mikael
authors.initials: CM
authors.lastname: Mattsson
authors.forename: Björn
authors.initials: B
authors.lastname: Ekblom
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.forename: Alison H
authors.initials: AH
authors.lastname: Harrill
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.forename: Björn
authors.initials: B
authors.lastname: Glinghammar
authors.forename: Ina
authors.initials: I
authors.lastname: Schuppe-Koistinen
mesh_terms: D000410:Alanine Transaminase / Q000097:blood*; D015415:Biomarkers / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000175:diagnosis*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D053538:Keratin-18 / Q000097:blood*; D035683:MicroRNAs / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D053538:Keratin-18; C577325:M65 antigen, human; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D010446:Peptide Fragments; D000410:Alanine Transaminase
keywords: HIV; acetaminophen; biomarkers; drug development; hepatotoxicity; liver; plasma; safety; toxicology; tuberculosis