MicroRNA-based discrimination of hepatotoxic and non-hepatotoxic drugs using a humanized liver mouse model.

Abstract

Drug-induced liver injury (DILI) is one of the most common adverse drug effects and a major cause of drug development failure. However, preclinically identifying drugs that cause liver injury remains difficult and represents a major challenge in drug development. MicroRNAs (miRNAs) have been proposed as biomarkers for the early detection of DILI owing to the dynamic changes in their expression in response to hepatotoxic insults. Therefore, identifying human-specific miRNAs that change early in response to diverse hepatotoxicants may enable a practical screening approach for drug development. Here, we evaluated whether hepatic miRNA responses can distinguish hepatotoxic from non-hepatotoxic drugs using a highly humanized liver chimeric mouse model (PXB-mouse). We administered eight hepatotoxic compounds (hTOX) and three non-hepatotoxic compounds (non-hTOX) to PXB-mice and performed a comprehensive analysis of the changes in hepatic RNA expression. PXB-mice exposed to hTOX exhibited an increased expression of liver mRNAs which were related to early activation of transcriptional pathways induced by liver damage. Among the miRNAs that exhibited expression changes exclusively in the hTOX-treated group but not in the non-hTOX group compared to the controls, we identified miR-4306 and miR-1237 as potential candidates of human-specific miRNAs whose expression was changed only after hTOX treatment. Although further validation studies are warranted, our findings suggest that detection of miR-4306 and miR-1237 in PXB-mice may help discriminate hepatotoxic from non-hepatotoxic drug exposure.