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.

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

“…Classic drugs with IDILI liability may act through activation of cytokines such as fas ligand (FasL), interferon γ (IFNγ) and TNF [96]. IFNγ is a soluble cytokine secreted by immune cells, and it exerts its effects by binding to transmembrane receptors on the surface of hepatocytes and Kupffer cells [96].…”

“…IFNγ is a soluble cytokine secreted by immune cells, and it exerts its effects by binding to transmembrane receptors on the surface of hepatocytes and Kupffer cells [96]. The biological effects of IFNγ stimulation are the induction of the major histocompatibility complex class I and II and of nitric oxide synthase (NOS) expression, stimulation of TNF production, and the upregulation of receptors for immunoglobulins, monocytes and/or macrophages [97].…”

“…An alternative hypothesis for IDILI is the multiple determinant hypothesis, which states that multiple risk factors (such as polymorphisms, age, gender, preexisting conditions) could overlap together to induce DILI [96,115,116]. The mouse model of halothane-induced liver toxicity can be used as an example.…”

“…This hypothesis of occurrences is known as the inflammatory stress hypothesis of IDILI. The inflammatory stress hypothesis has provided the first animal models in which pronounced liver injury is induced from numerous drugs associated with human IDILI, such as chlorpromazine, halothane, ranitidine, diclofenac, sulindac, and amiodarone [96,121,122]. However, the injury in this circumstance is very acute and does not have the latency features associated with human DILI from these drugs.…”

Drug-induced liver injury

“…Intrinsic DILI generally refers to direct toxic stress leading to cell death of hepatocytes 298 (sometimes sinusoidal endothelial cells are the principal target) mediated by a reactive 299 metabolite or a parent drug interfering with specific cell functions. This is mediated by increased 300 oxidative or redox stress, mitochondria dysfunction, endoplasmic reticulum (ER) stress, or DNA 301 damage 1,34,64,65 . As these progress unchecked, cell death occurs ( Figure 2 In contrast to intrinsic DILI, idiosyncratic DILI occurs in a small proportion of patients exposed to 325 a drug, reflecting the important contribution of the host mediated by genetic and environmental 326 factors.…”