A longitudinal assessment of miR-122 and GLDH as biomarkers of drug-induced liver injury in the rat

Petra Thulin, Robert James Hornby, Mariona Auli, Gunnar Nordahl, Daniel Antoine, Philip Starkey Lewis, Christopher E Goldring, B. Kevin Park , Neus Prats, Björn Glinghammar, Ina Schuppe-Koistinen

Research output: Contribution to journalArticlepeer-review

Abstract

CONTEXT: 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).

MATERIALS AND 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.

DISCUSSION AND 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.

Original languageEnglish
Pages (from-to)461-469
Number of pages9
JournalBiomarkers
Volume22
Issue number5
Early online date15 Dec 2016
DOIs
Publication statusPublished - Jul 2017

Keywords

  • Acetaminophen
  • Alanine Transaminase
  • Animals
  • Biomarkers
  • Chemical and Drug Induced Liver Injury
  • Early Diagnosis
  • Glutamate Dehydrogenase
  • MicroRNAs
  • Pharmacokinetics
  • Rats
  • Sensitivity and Specificity
  • Journal Article

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