title: Beyond miR-122: Identification of MicroRNA Alterations in Blood During a Time Course of Hepatobiliary Injury and Biliary Hyperplasia in Rats.
abstract: Identification of circulating microRNAs for the diagnosis of liver injury and as an indicator of underlying pathology has been the subject of recent investigations. While several studies have been conducted, with particular emphasis on miR-122, the timing of miRNA release into the circulation and anchoring to tissue pathology has not been systematically evaluated. In this study, miRNA profiling was conducted over a time course of hepatobiliary injury and repair using alpha-naphthylisothiocyanate (ANIT) and a proprietary compound, FP004BA. ANIT administration (50 mg/kg) to rats caused significant biliary epithelial cell and hepatocellular necrosis between 24 and 72 h, followed by resolution and progression to biliary hyperplasia by 120 h which was associated with miRNA release into the blood. FP004BA (100 mg/kg) was used to confirm associations of miRNA along a time course with similar hepatic pathology to ANIT. Treatment with ANIT or FP004BA resulted in significant alterations of overlapping miRNAs during the early and peak injury phases. In addition to well-characterized liver injury markers miR-122-5p and miR-192-5p, multiple members of the 200 family and the 101 family along with miR-802-5p and miR-30d-5p were consistently elevated during hepatobiliary injury caused by both toxicants, suggesting that these species may be potential biomarker candidates for hepatobiliary injury. After 14 days of dosing with 4BA, miR-182-5p remained elevated-while miR-122-5p and miR-192-5p had returned to baseline-suggesting that miR-182-5p may have added utility to monitor for hepatobiliary injury in the repair phases when there remains histological evidence of ongoing cellular injury.
authors.affiliation: *Hamner-UNC Institute for Drug Safety Sciences, RTP, North Carolina 27709;
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Church
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, LLC, Spring House, Pennsylvania 19477;
authors.forename: Monicah
authors.initials: M
authors.lastname: Otieno
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, LLC, San Diego, California 92121;
authors.forename: James Eric
authors.initials: JE
authors.lastname: McDuffie
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, LLC, Spring House, Pennsylvania 19477;
authors.forename: Bhanu
authors.initials: B
authors.lastname: Singh
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, LLC, Spring House, Pennsylvania 19477;
authors.forename: Manisha
authors.initials: M
authors.lastname: Sonee
authors.affiliation: Preclinical Development and Safety, Janssen Research & Development, LLC, Spring House, Pennsylvania 19477;
authors.forename: LeRoy
authors.initials: L
authors.lastname: Hall
authors.affiliation: *Hamner-UNC Institute for Drug Safety Sciences, RTP, North Carolina 27709;
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.affiliation: Investigational Toxicology, GDD-GED-Tox, Bayer Pharma AG, 42096 Wuppertal, Germany; and.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Ellinger-Ziegelbauer
authors.affiliation: *Hamner-UNC Institute for Drug Safety Sciences, RTP, North Carolina 27709; Department of Environmental and Occupational Health, The University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 ahharrill@uams.edu.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Harrill
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000494:pharmacology; D000818:Animals; D001659:Biliary Tract / Q000473:pathology*; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000473:pathology; D004195:Disease Models, Animal; D006965:Hyperplasia; D008099:Liver / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; C580643:MIRN122 microRNA, rat; D035683:MicroRNAs; D015058:1-Naphthylisothiocyanate
keywords: biliary hyperplasia; biomarkers; drug-induced liver injury; hepatobiliary injury; miRNA