Abstract
The genotoxic potential of drugs is a serious problem, and its evaluation is one of the most critical processes of drug development. Although the comet assay of compound-exposed tissue is a frequently used genotoxicity test, its high false-positive rate is a major complication, and we consistently obtained false-positive results using the comet assay of mouse liver for nine hepatotoxic non-genotoxins (NGTXs). To identify novel genotoxin (GTX)-specific biomarkers, we screened the expression of 750 microRNAs (miRNAs) in the livers of mice treated with GTXs or NGTXs. Three miRNAs, miR-22-3p, miR-409-3p, and miR-543-3p, were significantly down-regulated in GTX-treated mouse liver. In contrast, these three miRNAs were significantly up-regulated in plasma. A discrimination model based on the expression levels of these biomarkers successfully identified GTXs and NGTXs. This novel biomarker expression-based discrimination model analysis using both liver and plasma is effective for detecting genotoxicity with high sensitivity and reliability to support drug development.
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