An Impaired Immune Tolerance Animal Model Distinguishes the Potential of Troglitazone/Pioglitazone and Tolcapone/Entacapone to Cause IDILI

We have developed an animal model of amodiaquine-induced liver injury that has characteristics very similar to idiosyncratic drug-induced liver injury (IDILI) in humans by impairing immune tolerance using a PD1(-/-) mouse and cotreatment with anti-CTLA-4. In order to test the usefulness of this model as a general model for human IDILI risk, pairs of drugs with similar structures were tested, one of which is associated with a relatively high risk of IDILI and the other not. One such pair is troglitazone and pioglitazone; troglitazone has caused fatal cases of IDILI while pioglitazone is quite safe. Another pair is tolcapone and entacapone; tolcapone can cause serious IDILI; in contrast, although entacapone has been reported to cause liver injury, it is relatively safe. PD1(-/-) mice treated with anti-CTLA-4 and troglitazone or tolcapone displayed liver injury as determined by ALT levels and histology, while pioglitazone and entacapone showed less signs of liver injury. One possible mechanism by which drugs could induce an immune response leading to IDILI is by causing the release of danger-associated molecular pattern molecules that activate inflammasomes. We found that the supernatants from incubations of troglitazone, tolcapone, or entacapone with hepatocytes were also able to activate inflammasomes in macrophages, while the supernatant from pioglitazone incubations did not. These results are consistent with an immune mechanism for troglitazone-and tolcapone-induced IDILI and add to the evidence that this may be a general model for IDILI.