Mechanisms of idiosyncratic drug-induced liver injury

Uetrecht, Jack

doi:10.1016/bs.apha.2018.12.001

Cited by 49Drug-Induced Hepatotoxicity and ProtectionDrug-Induced Adverse ReactionsImmunotoxicology and immune responses

Mechanisms of idiosyncratic drug-induced liver injury

Uetrecht, Jack·2019·Advances in pharmacology

DOI 10.1016/bs.apha.2018.12.001

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Abstract

Idiosyncratic drug-induced liver injury (IDILI) is a significant problem. Little is known with certainty about the mechanisms of IDILI. However, there is growing evidence that most IDILI is immune mediated and caused by reactive metabolites. The two major and complementary hypotheses that link reactive metabolite formation with the induction of an immune response that can lead to IDILI are the hapten and danger hypotheses. Specifically, a reactive metabolite can bind to proteins and make them foreign; however, without activation of antigen presenting cells (APCs), the immune response will be immune tolerance. Not all reactive metabolites are associated with the same risk of causing IDILI. If the reactive metabolite can also cause some cell damage, this can lead to the release of danger-associated molecular pattern molecules (DAMPs) that activate APCs. Other hypotheses for the mechanism of IDILI include mitochondrial injury, inhibition of the bile salt export pump, and endoplasmic reticulum stress. These mechanisms may be complementary to the danger hypothesis in that they may cause the release of DAMPs. None of these hypotheses has been adequately tested. Previous animal models have had characteristics very different from IDILI in humans and are unlikely to involve the same mechanism. However, impairment of immune tolerance has led to a model with characteristics very similar to IDILI in humans. This will make it possible to rigorously test hypotheses. A better mechanistic understanding of IDILI should lead to better methods to screen drug candidates for IDILI risk and treat IDILI when it occurs.

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SMX-induced DILI is considered idiosyncratic as the mechanisms of injury are not fully understood, and toxicity occurs at therapeutic doses.
“SMX-induced DILI is considered idiosyncratic as the mechanisms of injury are not fully understood, and the toxicity occurs at therapeutic doses.3”
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Additional file 2 of Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity
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Authors: Uetrecht, J.
Affiliations: University of Toronto (CA)
Corresponding author: Uetrecht, Jack
ORCID: Uetrecht, Jack
Venue: Advances in pharmacology
Publisher: Elsevier
Published: 2019
Volume: 85
Pages: 133-163
ISSN: 1054-3589 (ISSN-L)
DOI: 10.1016/bs.apha.2018.12.001
OpenAlex: W2908736094
Cited by: 49
References: 101
Citations by year: 2026: 7 · 2025: 5 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 11 · 2020: 4
FWCI: 15.43
Type: book chapter
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Advances in pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords: idiosyncratic drug-induced liver injury, reactive drug metabolites, immune-mediated liver injury, antigen-presenting cells, immune tolerance, damage-associated molecular patterns, mitochondrial injury, endoplasmic reticulum stress, drug safety testing
MeSH terms: Animals, Disease Models, Animal, Drug Evaluation, Preclinical, Humans, Immune System, Liver, Metabolome, Chemical and Drug Induced Liver Injury

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Mechanisms of idiosyncratic drug-induced liver injury

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