Elsevier

Clinics in Liver Disease

Volume 17, Issue 4, November 2013, Pages 507-518
Clinics in Liver Disease

Mechanisms of Drug-induced Liver Injury

https://doi.org/10.1016/j.cld.2013.07.002Get rights and content

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Key points

  • •

    Idiosyncratic drug-induced liver injury (DILI) is the result of the interplay between the environment, drugs, and host (genetic, age, sex, immune factors, pre-existing diseases).

  • •

    Idiosyncratic DILI is often mediated by the adaptive immune response. Meanwhile, some drugs and metabolites can directly damage mitochondria, produce reactive oxygen species, and alter signaling pathway.

  • •

    To defend against the hazards induced by drugs, hepatocytes exhibit adaptive mechanisms, including upregulation of

Necrosis, apoptosis, and necroptosis

The fundamental process in DILI is the death of hepatocytes (in some circumstances, cholangiocytes or endothelial cells) in the background or recruitment of inflammation. DILI manifests clinically with hepatocellular injury, cholestasis, or a mixture of both.

Necrosis and apoptosis, theoretically, are 2 distinct modes of cell death. The fundamental differences between necrosis and apoptosis are the integrity of the plasma membrane, and involvement of caspase activation. Apoptosis is a sterile,

The involvement of reactive metabolites

The fact that liver is the central organ for drug metabolism places it as a prime target for reactive metabolites of drugs. In most cases, drugs or their reactive metabolites are detoxified via phase II conjugation (glucuronidation, acetylation, sulphation, glutathione conjugation) and excreted out of cells through multi-drug-resistance-associated protein transporters (phase III). Reactive metabolites are often produced through oxidation and reduction by cytochrome P450 (phase I). A balance

Involvement of stress signaling

JNK activation in response to TNF-α is usually rapidly dampened by NF-κB transcription of survival genes. Thus the activation is transient and often nontoxic. Sustained JNK activation, however, leads to lethal consequences. This sustained JNK activation has been extensively studied in the APAP mouse model. Inhibition of JNKs with a small synthetic molecule (SP600125) or silencing of JNK expression with siRNA protects against APAP hepatotoxicity.15, 29 JNK is a family of serine/threonine kinases

The involvement of mitochondrial dysfunction

The mechanisms of hepatocyte apoptosis and necrosis converge on mitochondria. The release of cytochrome C, apoptosis-inducing factor, and Smac from the mitochondrial intermembrane space are crucial to activate caspases and execute apoptosis in the presence of adequate ATP,33 which requires permeabilization of the outer mitochondrial membrane (OMM). Necrosis occurs via mitochondrial permeability transition (MPT). MPT is composed of voltage-dependent anion channel from OMM, adenine nucleotide

The involvement of mitochondrial adaptation

Mitochondria provide a primary energy source for the cell to function and cope with stress. Cyclical fusion and fission coupled with mitophagy are key in maintaining quality control and mitochondrial fitness.47 Mitochondrial fission is mediated by Drp1, a large GTPase in the dynamin family. Drp1 is recruited from cytosol by a group of adaptor proteins, including Mff, Mid49, and Mid51, and constricts both OMM and IMM at the site where mitochondria make contact with endoplasmic reticulum.

The role of adaptive immunity and innate immunity in DILI

Some DILI cases (for example, sulindac, phenytoin, and amoxicillin-clavulanic acid) have classic features of an allergic reaction, such as a rash, fever, and eosinophilia. The hypothesis is the drug or its metabolites act as haptens and covalently bind to a liver protein such as cytochrome p450. The drug-protein adducts are further processed in the macrophage/dendritic cell and presented as an antigen in complex with major histocompatibility complex class II molecules, triggering the adaptive

Summary

Idiosyncratic DILI is the result of the interplay between the environment, drugs, and host (genetic, age, sex, immune factors, pre-existing diseases) (Fig. 2). Idiosyncratic DILI is often mediated by the adaptive immune response. Meanwhile, some drugs and metabolites can directly damage mitochondria, produce ROS, and alter signaling pathway. To defend against the hazards induced by drugs, hepatocytes exhibit adaptive mechanisms including upregulation of Nrf2 signaling, mitophagy, and autophagy

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