Mathematical modelling reveals compound-specific stress pathway activity

Toxicology, vol. 518, pp. 154234

Abstract

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.

Authors 13

1. Elsje J Burgers Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands

2. Tamara Y Danilyuk Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands

3. Raju Prasad Sharma Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands

4. Andreas Verlohner

   BASF (Germany)

   Affiliation as printed

   BASF SE, RG/TE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen am Rhein, Germany

5. Nicole Rocker
   Affiliation as printed

   BASF Metabolome Solutions GmbH, Tegeler Weg 33, 10589 Berlin, Germany

6. Philipp Ternes
   Affiliation as printed

   BASF Metabolome Solutions GmbH, Tegeler Weg 33, 10589 Berlin, Germany

7. Lukas S. Wijaya Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands

8. Marcel Leist

   University of Konstanz

   Affiliation as printed

   In vitro Toxicology and Biomedicine, Department of Biology, University of Konstanz, Germany

9. Peter Bouwman Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands

10. Franziska Maria Zickgraf

    BASF (Germany)

    Affiliation as printed

    BASF SE, RG/TE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen am Rhein, Germany

11. Stefan Schildknecht

    Albstadt-Sigmaringen University

    Affiliation as printed

    Albstadt-Sigmaringen University, Faculty of Life Sciences, 72488, Sigmaringen, Germany

12. Bob van de Water Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

    Leiden University

    Affiliation as printed

    Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands

13. Joost B. Beltman corresponding Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

    Leiden University

    Affiliation as printed

    Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands. Electronic address: j.b.beltman@lacdr.leidenuniv.nl