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.

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“…In the analysis of drugs withdrawn for toxicity reasons in the period between 1992 and 2002, hepatotoxicity was identified in 27% of cases (36). Although mechanisms underlying most instances of drug-induced hepatotoxicity are still not well understood, different studies implicated factors such as host metabolism, detoxification, liver-regeneration, and immune response pathways (38,39).…”

An Update on Drug-induced Liver Injury

“…[39][40][41][42][43][44][45] They depend upon whether the hepatotoxicity is predictable or idiosyncratic ( Table 4). The predictable (or dose dependent) hepatotoxicity exemplified by paracetamol toxicity has been extensively investigated in animal models.…”

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“…Acetaminophen overdose in humans is the most common cause of drug-induced liver injury, which involves severe oxidative mitochondrial damage (23,24). Indeed, mitochondrial spheroids were readily detected in the livers of mice that received an overdosed amount of acetaminophen (Fig.…”