title: Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies.
abstract: MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver-specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases.
authors.affiliation: Investigative Toxicology and Pathology, Abbvie, North Chicago, IL, USA tatsiana.sharapova@abbvie.com.
authors.forename: T
authors.initials: T
authors.lastname: Sharapova
authors.affiliation: Exploratory Statistics, Abbvie, North Chicago, IL, USA.
authors.forename: V
authors.initials: V
authors.lastname: Devanarayan
authors.affiliation: Investigative Toxicology and Pathology, Abbvie, North Chicago, IL, USA.
authors.forename: B
authors.initials: B
authors.lastname: LeRoy
authors.affiliation: Cell, Molecular, and Exploratory Toxicology, Abbvie, North Chicago, IL, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Liguori
authors.affiliation: Investigative Toxicology and Pathology, Abbvie, North Chicago, IL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Blomme
authors.affiliation: Cell, Molecular, and Exploratory Toxicology, Abbvie, North Chicago, IL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Buck
authors.affiliation: Investigative Toxicology and Pathology, Abbvie, North Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Maher
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D004195:Disease Models, Animal; D005969:Glutamate Dehydrogenase / Q000097:blood; D008099:Liver / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014116:Toxicology
chemical_list: D015415:Biomarkers; C580643:MIRN122 microRNA, rat; D035683:MicroRNAs; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: biomarker; drug-induced liver injury; hepatotoxicity; histopathology; liver transaminases; microRNA; rat; serum; toxicology