Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies

• Published in: Veterinary pathology Vol. 53; no. 1; pp. 211 - 221
• Main Authors: Sharapova, T., Devanarayan, V., LeRoy, B., Liguori, M. J., Blomme, E., Buck, W., Maher, J.
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01-01-2016
• Subjects: Alanine Transaminase - blood; Animals; Aspartate Aminotransferases - blood; Biomarkers - blood; Chemical and Drug Induced Liver Injury - pathology; Disease Models, Animal; Glutamate Dehydrogenase - blood; Liver - pathology; Male; MicroRNAs - blood; Rats; Rats, Sprague-Dawley; Toxicology; toxicology; liver transaminases; drug-induced liver injury; rat; hepatotoxicity; histopathology; microRNA; biomarker; serum
• ISSN: 0300-9858; 1544-2217
• DOI: 10.1177/0300985815591076

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.