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Sci Rep. 2015 Oct 22;5:15501. doi: 10.1038/srep15501.

Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.

Author information

1
Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, UK.
2
Qiagen, Fredrick, Maryland, USA.
3
MRC Centre for Drug Safety Science, Department of Molecular &Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
4
Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
5
King's College London, London, UK.
6
Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
7
MRC Centre for Inflammation Research, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh.

Abstract

Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.

PMID:
26489516
PMCID:
PMC4614545
DOI:
10.1038/srep15501
[Indexed for MEDLINE]
Free PMC Article

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