Circulating microRNAs as potential markers of human drug‐induced liver injury

New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver‐enriched microRNAs (miR‐122 and miR‐192) are promising biomarkers of acetaminophen‐induced acute liver injury (APAP‐ALI) in mice. We have examined these...

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Published in:Hepatology (Baltimore, Md.) Vol. 54; no. 5; pp. 1767 - 1776
Main Authors: Starkey Lewis, Philip J., Dear, James, Platt, Vivien, Simpson, Kenneth J., Craig, Darren G.N., Antoine, Daniel J., French, Neil S., Dhaun, Neeraj, Webb, David J., Costello, Eithne M., Neoptolemos, John P., Moggs, Jonathan, Goldring, Chris E., Park, B. Kevin
Format: Journal Article
Language:English
Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2011
Wiley
Wolters Kluwer Health, Inc
Subjects:
Acetaminophen - poisoning
Acute Disease
Adolescent
Adult
Aged
Alanine Transaminase - blood
Analgesics, Non-Narcotic - poisoning
Biological and medical sciences
Biomarkers
Biomarkers - blood
Chemical and Drug Induced Liver Injury - blood
Chemical and Drug Induced Liver Injury - diagnosis
Chemical and Drug Induced Liver Injury - surgery
Diagnostic Techniques, Digestive System
Drug toxicity and drugs side effects treatment
Female
Gastroenterology. Liver. Pancreas. Abdomen
Hepatology
Humans
Liver
Liver Transplantation
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Male
Medical sciences
MicroRNAs
MicroRNAs - blood
Middle Aged
Pharmacology. Drug treatments
Prospective Studies
Toxicity: digestive system
Young Adult
Human
Digestive diseases
Hepatic disease
Hepatotoxicity
Gastroenterology
ISSN:0270-9139, 1527-3350, 1527-3350
Online Access:Get full text
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Summary:New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver‐enriched microRNAs (miR‐122 and miR‐192) are promising biomarkers of acetaminophen‐induced acute liver injury (APAP‐ALI) in mice. We have examined these molecules, for the first time, in humans with APAP poisoning. Serum miR‐122 and miR‐192 were substantially higher in APAP‐ALI patients, compared to healthy controls (median ΔΔCt [25th, 75th percentile]) (miR‐122: 1,265 [491, 4,270] versus 12.1 [7.0, 26.9], P < 0.0001; miR‐192: 6.9 [2.0, 29.2] versus 0.44 [0.30, 0.69], P < 0.0001). A heart‐enriched miR‐1 showed no difference between APAP‐ALI patients and controls, whereas miR‐218 (brain‐enriched) was slightly higher in the APAP‐ALI cohort (0.17 [0.07, 0.50] versus 0.07 [0.04, 0.12]; P = 0.01). In chronic kidney disease (CKD) patients, miR‐122 and ‐192 were modestly higher, compared to controls (miR‐122: 32.0 [21.1, 40.9] versus 12.1 [7.0, 26.9], P = 0.006; miR‐192: 1.2 [0.74, 1.9] versus 0.44 [0.30, 0.69], P = 0.005), but miR‐122 and ‐192 were substantially higher in APAP‐ALI patients than CKD patients (miR‐122: P < 0.0001; miR‐192: P < 0.0004). miR‐122 correlated with peak ALT levels in the APAP‐ALI cohort (Pearson R = 0.46, P = 0.0005), but not with prothrombin time. miR‐122 was also raised alongside peak ALT levels in a group of patients with non‐APAP ALI. Day 1 serum miR‐122 levels were almost 2‐fold higher in APAP‐ALI patients who satisfied King's College Criteria (KCC), compared to those who did not satisfy KCC, although this did not reach statistical significance (P = 0.15). Conclusion: This work provides the first evidence for the potential use of miRNAs as biomarkers of human drug‐induced liver injury. (HEPATOLOGY 2011;)
Bibliography:Joint first author.
Part of this work was funded by Novartis in the form of a PhD studentship (to P.S.L.) as part of the Center for Drug Safety Science supported by the Medical Research Council (grant no.: G0700654).
fax: +44 (0)151 794 5540
Joint last author.
Potential conflict of interest: Nothing to report.
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ISSN:0270-9139
1527-3350
1527-3350
DOI:10.1002/hep.24538