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Mechanisms of drug-induced liver injury: from bedside to bench

Abstract

The low incidence of idiosyncratic drug-induced liver injury (DILI), together with the lack of a reliable diagnostic biomarker and robust preclinical and in vitro toxicology test systems for the condition have limited our ability to define the mechanisms of DILI. A notable exception is acetaminophen hepatotoxicity, which is associated with the formation of a well-characterized and highly reactive intermediate metabolite, N-acetyl-p-benzoquinone imine. However, studies have also suggested a role for the host immune response and variation in the expression of the lymphocyte CD44 gene in the pathogenesis of acetaminophen hepatotoxicity. A careful review of the laboratory, clinical and histological phenotype of patients with DILI can provide potential clues to the mechanisms of disease pathogenesis, as observed with fialuridine and valproate hepatotoxicity. In addition, the use of transcriptomic and genomic approaches in patients with well-characterized DILI has provided important insights into the involvement of the host immune response in the pathogenesis of hepatotoxicity associated with the administration of flucloxacillin, lumiracoxib or ximelagatran. This Review highlights new developments regarding the potential role of reactive metabolites, mitochondrial toxicity, host immune-response pathways and biliary transporters in the etiopathogenesis of DILI. Going forward, a bedside-to-bench approach could improve our understanding of the mechanisms and risk factors for DILI.

Key Points

  • The biological basis for most instances of drug-induced liver injury (DILI) is unknown, but variation in host metabolic, detoxification, liver-regeneration and immune-response pathways has been implicated

  • Results of studies in animal models and humans suggest a role for variation in the expression of CD44 in acetaminophen hepatotoxicity

  • Genomic approaches have demonstrated that variation in the host immune response could help to explain susceptibility to DILI induced by treatment with ximelagatran, lumiracoxib or flucloxacillin

  • Informative animal models of DILI and in vitro test systems to predict drug hypersensitivity reactions are currently lacking

  • A bedside-to-bench approach involving the collection of biological samples from patients with well-characterized DILI could improve our understanding of the risk factors and mechanisms of DILI

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Figure 1: Potential risk factors involved in the pathogenesis of DILI.
Figure 2: Mechanism of acetaminophen hepatotoxicity.
Figure 3: Function of hepatobiliary transporters.
Figure 4: Role of the host immune response in the pathogenesis of DILI.

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S. Tujios and R. F. Fontana contributed equally to researching data for the article, discussing the content, writing and reviewing/editing the manuscript before submission.

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Correspondence to Robert J. Fontana.

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R. J. Fontana has been a Consultant for GlaxoSmithKline and Vertex Pharmaceuticals, and has been on the Speaker's bureau for Genentech and Gilead Sciences. S. Tujios declares no competing interests.

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Tujios, S., Fontana, R. Mechanisms of drug-induced liver injury: from bedside to bench. Nat Rev Gastroenterol Hepatol 8, 202–211 (2011). https://doi.org/10.1038/nrgastro.2011.22

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