PT  - JOURNAL ARTICLE
AU  - Robert A. Roth
AU  - Ashley R. Maiuri
AU  - Patricia E. Ganey
TI  - Idiosyncratic Drug-Induced Liver Injury: Is Drug-Cytokine Interaction the Linchpin?
AID  - 10.1124/jpet.116.237578
DP  - 2017 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 368--377
VI  - 360
IP  - 2
4099  - http://jpet.aspetjournals.org/content/360/2/368.short
4100  - http://jpet.aspetjournals.org/content/360/2/368.full
SO  - J Pharmacol Exp Ther2017 Feb 01; 360
AB  - Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete knowledge of mechanisms that underlie these adverse responses. Several hypotheses involving adaptive immune responses, inflammatory stress, inability to adapt to stress, and multiple, concurrent factors have been proposed. Yet much remains unknown about how drugs interact with the liver to effect death of hepatocytes. Evidence supporting hypotheses implicating adaptive or innate immune responses in afflicted patients has begun to emerge and is bolstered by results obtained in experimental animal models and in vitro systems. A commonality in adaptive and innate immunity is the production of cytokines, including interferon-γ (IFNγ). IFNγ initiates cell signaling pathways that culminate in cell death or inhibition of proliferative repair. Tumor necrosis factor-α, another cytokine prominent in immune responses, can also promote cell death. Furthermore, tumor necrosis factor-α interacts with IFNγ, leading to enhanced cellular responses to each cytokine. In this short review, we propose that the interaction of drugs with these cytokines contributes to idiosyncratic drug-induced liver injury, and mechanisms by which this could occur are discussed.