Drugs Associated with Idiosyncratic Hepatotoxicity Synergize with Cytokines to Kill Hepatocytes in Vitro

Idiosyncratic drug‐induced liver injury (IDILI) occurs in a small fraction of patients and often results in removal of otherwise efficacious drugs from the market. The mechanisms of IDILI are unknown; however, in studies using animal models the inflammatory mediators tumor necrosis factor‐alpha (TNFα) and interferon‐gamma (IFNγ) are essential to the pathogenesis of liver injury. The purpose of this study was to test the hypothesis that a drug's ability to synergize with inflammatory cytokines to kill hepatocytes in vitro can classify dugs according to their potential to cause idiosyncratic hepatotoxicity in humans. Human hepatoma (HepG2) cells were treated with drugs associated with IDILI or with drugs lacking IDILI liability and cotreated with TNFα and/or IFNγ.Of 13 drugs associated with IDILI, 12 synergized with TNFα to kill HepG2 cells.IFNγ enhanced the toxicity mediated by 8 IDILI‐positive drugs in the presence of TNFα. Of 10 drugs with little/no IDILI potential, none synergized with inflammatory cytokines to kill HepG2 cells. These findings indicate that drugs associated with IDILI in humans synergize with TNFα and IFNγ in vitro to cause cell death and raise the possibility that drug‐cytokine synergy underlies hepatocellular killing in some IDILI reactions. These results suggest an in vitro approach that could be used during preclinical safety evaluation to identify drug candidates with the potential to cause IDILI.