title: Circulating microRNAs as potential markers of human drug-induced liver injury.
abstract: 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).
  
  
  CONCLUSIONS
  This work provides the first evidence for the potential use of miRNAs as biomarkers of human drug-induced liver injury.
authors: MRC Center for Drug Safety Science, Department of Clinical and Molecular Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors: Philip J
authors: PJ
authors: Starkey Lewis
authors: James
authors: J
authors: Dear
authors: Vivien
authors: V
authors: Platt
authors: Kenneth J
authors: KJ
authors: Simpson
authors: Darren G N
authors: DG
authors: Craig
authors: Daniel J
authors: DJ
authors: Antoine
authors: Neil S
authors: NS
authors: French
authors: Neeraj
authors: N
authors: Dhaun
authors: David J
authors: DJ
authors: Webb
authors: Eithne M
authors: EM
authors: Costello
authors: John P
authors: JP
authors: Neoptolemos
authors: Jonathan
authors: J
authors: Moggs
authors: Chris E
authors: CE
authors: Goldring
authors: B Kevin
authors: BK
authors: Park
mesh_terms: D000082:Acetaminophen / Q000506:poisoning*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000506:poisoning; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis* / Q000601:surgery; D003938:Diagnostic Techniques, Digestive System; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D018712:Analgesics, Non-Narcotic; D015415:Biomarkers; C531907:MIRN122 microRNA, human; C546783:MIRN192 microRNA, human; D035683:MicroRNAs; D000082:Acetaminophen; D000410:Alanine Transaminase