Abstract
Idiosyncratic, drug-induced liver injury (IDILI) is a human health problem for which we have limited understanding of mechanisms. Evidence from patients suggests a contribution of the immune system, and in animal models, inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN), play a critical role. We have been investigating the mechanisms by which TNF and IFN interact with drugs to cause hepatocellular damage in vitro. Trovafloxacin (TVX), a drug associated with IDILI, induced cell death in a human hepatocyte cell line (HepG2) only in the presence of TNF. Cell death was associated with DNA damage, replication stress and activation of the mitogen-activated protein kinases JNK and ERK. Interference with these pathways attenuated cell death. Diclofenac, another drug that causes IDILI, also kills hepatocytes in the presence of TNF. IFN augments cell death from TNF/diclofenac. The mechanism of cell death from cytokine interaction with diclofenac also involves activation of JNK and ERK, as well as induction of endoplasmic reticulum stress. Furthermore, JAK/STAT signaling and calcium are important in this cytotoxicity. Understanding mechanisms of cytotoxic drug-cytokine interaction could increase our knowledge of causes of IDILI in people and might also serve as the basis for preclinical identification of drug candidates with IDILI potential. (Research supported by NIH DK112695)
