Cited by 403Drug-Induced Hepatotoxicity and ProtectionPharmacogenetics and Drug MetabolismPharmacovigilance and Adverse Drug Reactions

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Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

Boelsterli, U·2003·Toxicology and Applied Pharmacology

DOI 10.1016/s0041-008x(03)00368-5

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Abstract

The nonsteroidal antiinflammatory drug diclofenac causes rare but significant cases of serious hepatotoxicity, typically with a delayed onset (>1-3 months). Because there is no simple dose relationship and because liver injury cannot be reproduced in current animal models, individual patient-specific susceptibility factors have been evoked to account for the increased risk. While these patient factors have remained undefined, a number of molecular hazards have been characterized. Among these are metabolic factors (bioactivation by hCYP2C9 or hCYP3A4 to thiol-reactive quinone imines, activation by hUGT2B7 to protein-reactive acyl glucuronides and iso-glucuronides, and 4'-hydroxylation secondary to diclofenac glucuronidation), as well as kinetic factors (Mrp2-mediated concentrative transport of diclofenac metabolites into bile). From the toxicodynamic view, both oxidative stress (caused by putative diclofenac cation radicals or nitroxide and quinone imine-related redox cycling) and mitochondrial injury (protonophoretic activity and opening of the permeability transition pore) alone or in combination have been implicated in diclofenac toxicity. In some cases, immune-mediated liver injury is involved, inferred from inadvertent rechallenge data and from a number of experiments demonstrating T cell sensitization. Why certain underlying diseases (e.g., osteoarthritis) also increase the susceptibility to diclofenac hepatotoxicity is not clear. To date, cumulative damage to mitochondrial targets seems a plausible putative mechanism to explain the delayed onset of liver failure, perhaps even superimposed on an underlying silent mitochondrial abnormality. Increased efforts to identify both patient-specific risk factors and disease-related factors will help to define patient subsets at risk as well as increase the predictability of unexpected hepatotoxicity in drug development.

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Authors: Boelsterli, U.
Affiliations: University of Basel (CH)
Corresponding author: Boelsterli, U
Venue: Toxicology and Applied Pharmacology
Publisher: Elsevier BV
Published: 2003-11-01
Volume: 192
Issue: 3
Pages: 307-322
ISSN: 0041-008X (ISSN-L)
DOI: 10.1016/s0041-008x(03)00368-5
OpenAlex: W2003181581
Cited by: 403
References: 101
Citations by year: 2026: 11 · 2025: 10 · 2024: 8 · 2023: 17 · 2022: 12 · 2021: 20 · 2020: 17 · 2019: 18 · 2018: 15 · 2017: 23 · 2016: 30 · 2015: 17 · 2014: 17 · 2013: 20 · 2012: 20
FWCI: 8.24
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Toxicology and Applied Pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
Keywords: diclofenac, hepatotoxicity, idiosyncratic drug toxicity, nonsteroidal anti-inflammatory drugs, CYP2C9, CYP3A4, UGT2B7, quinone imines, acyl glucuronides, MRP2, bile transport, oxidative stress, mitochondrial injury, mitochondrial permeability transition pore, immune-mediated liver injury, T cell sensitization, osteoarthritis, toxicodynamics
MeSH terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, Diclofenac, Humans, Chemical and Drug Induced Liver Injury, Drug-Related Side Effects and Adverse Reactions

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Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

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