Abstract
Unpredictable drug-induced liver injury (DILI) is currently the major cause for discontinuations of new candidates in development or for withdrawals of drugs from the market, but it is difficult to predict DILI risk in humans based on preclinical safety evaluations using conventional experimental animals. On the basis of the accumulating recent knowledge of immune systems in hepatic pathology, immune-mediated DILI is recognized to cause an imbalance of differentiated T cells. Recently, we reported the relationship between expression changes of Th cell differentiation- and inflammation-related factors in our established mouse DILI models of halothane, phenytoin, dicloxacillin, diclofenac, carbamazepine, flutamide, and methimazole.
Little is known about the role of individual miRNA and its target involved in immune- and inflammation-related response in DILI. Th17-type immune responses had been reported in halothane (HAL)-induced liver injury in mice. Although the peak of ALT level is shown 24 h after the HAL administration, the miRNA gene down regulation that occurred 1 h after HAL administration was primarily related to inflammation- and immune-related DILI. Up-regulation of STAT3 by miR-106b was critical for the pathogenesis of HAL-induced liver injury. The similar miRNA story was demonstrated in Th2-type immune response using a methimazole (MTZ)-induced liver injury mouse model. Negative regulations of the expression of SRY-related HMG-box 4 (SOX4) by miR-29b-1-5p and that of lymphoid enhancer factor-1 (LEF1) by miR-449a-5p were suggested to play an important role for development of Th2 bias in the early phase of MTZ-induced liver injury. Key immune-related regulatory events occur during the early phase of toxicity. MiRNA involved in regulatory mechanisms of toxicological signal cascades and could be predictive biomarkers in the early phase of DILI.
