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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Vydáno v:	Hepatology (Baltimore, Md.) Ročník 54; číslo 5; s. 1767 - 1776
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2011 Wiley Wolters Kluwer Health, Inc
Témata:	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
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Shrnutí:	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;)
Bibliografie:	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. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0270-9139 1527-3350 1527-3350
DOI:	10.1002/hep.24538