title: A longitudinal assessment of miR-122 and GLDH as biomarkers of drug-induced liver injury in the rat.
abstract: BACKGROUND
  There is an ongoing search for specific and translational biomarkers of drug-induced liver injury (DILI). MicroRNA-122 (miR-122) has previously shown potential as a sensitive, specific, and translational biomarker of DILI in both rodent, and human studies.
  
  
  OBJECTIVE
  To build on previous work within the field, we examined biomarker kinetics in a rat model of acetaminophen (APAP)-induced liver injury to confirm the sensitivity, and specificity of miR-122 and glutamate dehydrogenase (GLDH).
  
  
  METHODS
  qRT-PCR and a standard enzymatic assay were used for biomarker analysis.
  
  
  RESULTS
  Both miR-122 and GLDH were demonstrated to be more readily-detectable biomarkers of APAP-DILI than alanine aminotransferase (ALT). Peak levels for all biomarkers were detected at 2 days after APAP. At day 3, miR-122 had returned to baseline; however, other biomarkers remained elevated between 3 and 4 days. We were also able to demonstrate that, although miR-122 is present in greater quantities in exosome-free form, both exosome-bound and non-vesicle bound miR-122 are released in a similar profile throughout the course of DILI.
  
  
  CONCLUSIONS
  Together, this study demonstrates that both GLDH and miR-122 could be used during preclinical drug-development as complementary biomarkers to ALT to increase the chance of early detection of hepatotoxicity.
authors.affiliation: a Drug Safety & Metabolism , Discovery Safety, AstraZeneca , Mölndal , Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Thulin
authors.affiliation: b MRC Centre for Drug Safety Science , University of Liverpool , Liverpool, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hornby
authors.affiliation: c Pathology and Predictive Toxicology Section , Almirall , Barcelona , Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Auli
authors.affiliation: d Operations , AstraZeneca , Södertälje , Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Nordahl
authors.affiliation: b MRC Centre for Drug Safety Science , University of Liverpool , Liverpool, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Antoine
authors.affiliation: e MRC Centre for Regenerative Medicine , University of Edinburgh , Edinburgh , UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Starkey Lewis
authors.affiliation: e MRC Centre for Regenerative Medicine , University of Edinburgh , Edinburgh , UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Goldring
authors.affiliation: e MRC Centre for Regenerative Medicine , University of Edinburgh , Edinburgh , UK.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.affiliation: c Pathology and Predictive Toxicology Section , Almirall , Barcelona , Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Prats
authors.affiliation: f Swedish Toxicology Sciences Research Center (Swetox) , Karolinska Institutet , Södertälje , Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Glinghammar
authors.affiliation: g Department of Physiology and Pharmacology, Science for Life Laboratory , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Ina
authors.initials: I
authors.lastname: Schuppe-Koistinen
mesh_terms: D000082:Acetaminophen; D000410:Alanine Transaminase; D000818:Animals; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis*; D042241:Early Diagnosis; D005969:Glutamate Dehydrogenase / Q000097:blood; D035683:MicroRNAs / Q000097:blood; D010599:Pharmacokinetics; D051381:Rats; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; C580643:MIRN122 microRNA, rat; D035683:MicroRNAs; D000082:Acetaminophen; D005969:Glutamate Dehydrogenase; D000410:Alanine Transaminase
keywords: ALT; GLDH; Hepatotoxicity; acetaminophen; exosomes; miR-122