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NPJ Syst Biol Appl. 2018 Jun 11;4:23. doi: 10.1038/s41540-018-0058-z. eCollection 2018.

Model-based identification of TNFα-induced IKKβ-mediated and IκBα-mediated regulation of NFκB signal transduction as a tool to quantify the impact of drug-induced liver injury compounds.

Author information

1
1Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
2Institute of Physics, University of Freiburg, Freiburg, Germany.
3
3Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
4
4MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
5
5Institute of Physical and Theoretical Chemistry, Single Molecule Biophysics, Johann Wolfgang Goethe-University, Frankfurt, Germany.
6
6North Western Hepatobiliary Unit, Aintree University Hospital NHS Foundation Trust, Liverpool, UK.
7
7Bioquant, University of Heidelberg, Heidelberg, Germany.
8
8BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
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Contributed equally

Abstract

Drug-induced liver injury (DILI) has become a major problem for patients and for clinicians, academics and the pharmaceutical industry. To date, existing hepatotoxicity test systems are only poorly predictive and the underlying mechanisms are still unclear. One of the factors known to amplify hepatotoxicity is the tumor necrosis factor alpha (TNFα), especially due to its synergy with commonly used drugs such as diclofenac. However, the exact mechanism of how diclofenac in combination with TNFα induces liver injury remains elusive. Here, we combined time-resolved immunoblotting and live-cell imaging data of HepG2 cells and primary human hepatocytes (PHH) with dynamic pathway modeling using ordinary differential equations (ODEs) to describe the complex structure of TNFα-induced NFκB signal transduction and integrated the perturbations of the pathway caused by diclofenac. The resulting mathematical model was used to systematically identify parameters affected by diclofenac. These analyses showed that more than one regulatory module of TNFα-induced NFκB signal transduction is affected by diclofenac, suggesting that hepatotoxicity is the integrated consequence of multiple changes in hepatocytes and that multiple factors define toxicity thresholds. Applying our mathematical modeling approach to other DILI-causing compounds representing different putative DILI mechanism classes enabled us to quantify their impact on pathway activation, highlighting the potential of the dynamic pathway model as a quantitative tool for the analysis of DILI compounds.

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