Mathematical modelling reveals compound-specific stress pathway activity

Drug-induced liver injury (DILI) is a major problem for the drug development industry. It has been suggested that activation of stress pathways within cells is an important indicator of DILI. In this project, we aimed to develop a mathematical model of invoked stress responses by three compounds wit...

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Published in:Toxicology (Amsterdam) Vol. 518; p. 154234
Main Authors: Burgers, Elsje J., Danilyuk, Tamara Y., Sharma, Raju P., Renner, Nadine, Verlohner, Andreas, Rocker, Nicole, Ternes, Philipp, Wijaya, Lukas S., Leist, Marcel, Bouwman, Peter, Zickgraf, Franziska M., Schildknecht, Stefan, van de Water, Bob, Beltman, Joost B.
Format: Journal Article
Language:English
Published: Ireland Elsevier B.V 01.12.2025
Subjects:
Chemical and Drug Induced Liver Injury - etiology
Chemical and Drug Induced Liver Injury - metabolism
Diclofenac - toxicity
DILI
Emergency
Glutathione - metabolism
Hep G2 Cells
Humans
Integrated stress response
Ketoconazole - toxicity
Mathematical modelling
Models, Biological
Nitrofurantoin - toxicity
Oxidative Stress - drug effects
Oxidative stress response
Pharmacology/Toxicology
Signal Transduction - drug effects
DILI
Mathematical modelling
Integrated stress response
Oxidative stress response
ISSN:0300-483X, 1879-3185, 1879-3185
Online Access:Get full text
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Summary:Drug-induced liver injury (DILI) is a major problem for the drug development industry. It has been suggested that activation of stress pathways within cells is an important indicator of DILI. In this project, we aimed to develop a mathematical model of invoked stress responses by three compounds with high DILI liability: nitrofurantoin, diclofenac and ketoconazole. To this end, we used imaging data from HepG2 cells and cell-associated compound and intracellular glutathione measurements. We initially developed a model for the integrated and oxidative stress responses following nitrofurantoin exposure. Subsequently, we expanded this to simulate responses to diclofenac and ketoconazole. To apply the model to these compounds multiple parameters required recalibration, yet the structure of the model was unchanged. Our analysis shows that the magnitude of interactions between transcription factors and downstream targets can differ even when the activated pathways are the same.
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ISSN:0300-483X
1879-3185
1879-3185
DOI:10.1016/j.tox.2025.154234