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

Boelsterli, U

doi:10.1016/s0041-008x(03)00368-5

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

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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Genetic polymorphisms, drug overdosage, or interactions with other medications can lead to variations in the activity of these enzymes, thereby influencing the metabolic rate of diclofenac and the generation of toxic intermediates, ultimately increasing the risk of liver toxicity.
“Genetic polymorphisms, drug overdosage, or interactions with other medications can lead to variations in the activity of these enzymes, thereby influencing the metabolic rate of diclofenac and the generation of toxic intermediates, ultimately increasing the risk of liver toxicity [28,29].”
From Decellularized liver scaffolds for constructing drug-metabolically functional ex vivo human liver models (2025) · cites this paper as [28]
Diclofenac is biotransformed primarily through specific drug-metabolizing enzymes, including members of the CYP family such as CYP2C9 and CYP3A4.
“Previous studies have shown that diclofenac is biotransformed primarily through specific drug-metabolizing enzymes, including members of the CYP family such as CYP2C9 and CYP3A4.”
From Decellularized liver scaffolds for constructing drug-metabolically functional ex vivo human liver models (2025) · cites this paper as [28]

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Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective
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Intrinsic versus Idiosyncratic Drug-Induced Hepatotoxicity—Two Villains or One?
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Modest Inflammation Enhances Diclofenac Hepatotoxicity in Rats: Role of Neutrophils and Bacterial Translocation
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Oxidative Stress as a Mechanism of Valproic Acid-Associated Hepatotoxicity
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Hepatocytes—the choice to investigate drug metabolism and toxicity in man: In vitro variability as a reflection of in vivo
Gómez-Lechón, M. J., Castell, J. V., & Donato, M. T. (2006) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2006.10.013 · Cited by 150 · see citing works
New Insights into Toxicity and Drug Testing
Gowder, S. J. (2013) · InTech eBooks · doi:10.5772/55886 · Cited by 149 · see citing works
The Endoplasmic Reticulum in Xenobiotic Toxicity
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Diclofenac photodegradation under simulated sunlight: Effect of different forms of nitrogen and Kinetics
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Metabolic Profiling of the Response to an Oral Glucose Tolerance Test Detects Subtle Metabolic Changes
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A perfusion incubator liver chip for 3D cell culture with application on chronic hepatotoxicity testing
Yu, F., Deng, R., Tong, W. H., Li, H., Ng, C. W., IslamBadhan, A., Iliescu, C., & Yu, H. (2017) · Scientific Reports · doi:10.1038/s41598-017-13848-5 · Cited by 125 · see citing works
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Idiosyncratic Drug-Induced Liver Injury and the Role of Inflammatory Stress with an Emphasis on an Animal Model of Trovafloxacin Hepatotoxicity
Shaw, P. J., Ganey, P. E., & Roth, R. A. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq168 · Cited by 123 · see citing works
A Predictive Ligand-Based Bayesian Model for Human Drug-Induced Liver Injury
Ekins, S., Williams, A. J., & Xu, J. J. (2010) · Drug Metabolism and Disposition · doi:10.1124/dmd.110.035113 · Cited by 122 · see citing works
In Vitro Evaluation of Potential Hepatotoxicity Induced by Drugs
Gómez-Lechón, M. J., Lahoz, A., Gombau, L., Castell, J. V., & Donato, M. T. (2010) · Current Pharmaceutical Design · doi:10.2174/138161210791208910 · Cited by 121 · see citing works
Drug-induced fatty liver disease: An overview of pathogenesis and management
Satapathy, S. K., Kuwajima, V. K., Nadelson, J., Atiq, O., & Sanyal, A. J. (2015) · Annals of Hepatology · doi:10.5604/16652681.1171749 · Cited by 120 · see citing works
Magnetic quaternary chitosan hybrid nanoparticles for the efficient uptake of diclofenac from water
Soares, S. F., Fernandes, T. P., Sacramento, M. M. A., Trindade, T., & Daniel‐da‐Silva, A. L. (2018) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2018.09.030 · Cited by 118 · see citing works
Signal Transduction Pathways Involved in Drug-Induced Liver Injury
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Randomized Controlled Trial of Diclofenac Sodium Gel in Knee Osteoarthritis
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Electrochemical investigations of diclofenac at edge plane pyrolytic graphite electrode and its determination in human urine
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Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin
Liguori, M. J., Anderson, M. G., Bukofzer, S., McKim, J. M., Pregenzer, J. F., Retief, J., Spear, B. B., & Waring, J. F. (2005) · Hepatology · doi:10.1002/hep.20514 · Cited by 110 · see citing works
Idiosyncratic Toxicity: A Convergence of Risk Factors
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Anti-inflammatory drugs in the marine environment: Bioconcentration, metabolism and sub-lethal effects in marine bivalves
Almeida, Â., Solé, M., Soares, A. M. V. M., & Freitas, R. (2020) · Environmental Pollution · doi:10.1016/j.envpol.2020.114442 · Cited by 108 · see citing works
Evaluation of ecotoxicological effects of drugs on Daphnia magna using different enzymatic biomarkers
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Toxic effects of diclofenac on life history parameters and the expression of detoxification-related genes in Daphnia magna
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Oxidative stress as a mechanism underlying sulfasalazine-induced toxicity
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Diclofenac inhibits tumor necrosis factor-α-induced nuclear factor-κB activation causing synergistic hepatocyte apoptosis
Fredriksson, L., Herpers, B., Benedetti, G., Matadin, Q., Puigvert, J. C., de Bont, H., Dragović, S., Vermeulen, N. P. E., Commandeur, J. N. M., Danen, E. H. J., et al. (2011) · Hepatology · doi:10.1002/hep.24314 · Cited by 100 · see citing works
Toxicity of Carboxylic Acid-Containing Drugs: The Role of Acyl Migration and CoA Conjugation Investigated
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Calcium Signaling in Liver Injury and Regeneration
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A review of important heavy metals toxicity with special emphasis on nephrotoxicity and its management in cattle
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Hepatic Clearance of Reactive Glucuronide Metabolites of Diclofenac in the Mouse Is Dependent on Multiple ATP-Binding Cassette Efflux Transporters
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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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