Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury.
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.
Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, UK.
A D B
AD
Vliegenthart
Qiagen, Fredrick, Maryland, USA.
J M
JM
Shaffer
MRC Centre for Drug Safety Science, Department of Molecular &Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
J I
JI
Clarke
Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, UK.
L E J
LE
Peeters
Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, UK.
A
A
Caporali
Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, UK.
D N
DN
Bateman
Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, UK.|King's College London, London, UK.
D M
DM
Wood
Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, UK.|King's College London, London, UK.
P I
PI
Dargan
Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
D G
DG
Craig
Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
J K
JK
Moore
MRC Centre for Inflammation Research, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh.
A I
AI
Thompson
MRC Centre for Inflammation Research, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh.
N C
NC
Henderson
Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, UK.
D J
DJ
Webb
MRC Centre for Drug Safety Science, Department of Molecular &Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
J
J
Sharkey
MRC Centre for Drug Safety Science, Department of Molecular &Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
D J
DJ
Antoine
MRC Centre for Drug Safety Science, Department of Molecular &Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
B K
BK
Park
Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, UK.
M A
MA
Bailey
Qiagen, Fredrick, Maryland, USA.
E
E
Lader
Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
K J
KJ
Simpson
Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh University, UK.
J W
JW
Dear
D000082:Acetaminophen / Q000009:adverse effects* / Q000627:therapeutic use; D058186:Acute Kidney Injury / Q000097:blood* / Q000139:chemically induced; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics
D015415:Biomarkers; D035683:MicroRNAs; D000082:Acetaminophen; D000410:Alanine Transaminase