title: Idiosyncratic Drug-Induced Liver Injury: Is Drug-Cytokine Interaction the Linchpin?
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan rothr@msu.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Maiuri
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016207:Cytokines; D004364:Pharmaceutical Preparations