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



Oppelt, Angela, Kaschek, Daniel, Huppelschoten, Suzanna, Sison-Young, Rowena, Zhang, Fang, Buck-Wiese, Marie, Herrmann, Franziska, Malkusch, Sebastian, Kruger, Carmen L, Meub, Mara
et al (show 12 more authors) (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. NPJ SYSTEMS BIOLOGY AND APPLICATIONS, 4 (1). 23-.

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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.

Item Type: Article
Uncontrolled Keywords: Digestive Diseases, Chronic Liver Disease and Cirrhosis, Liver Disease, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, 2 Aetiology, 5 Development of treatments and therapeutic interventions, Oral and gastrointestinal
Depositing User: Symplectic Admin
Date Deposited: 13 Sep 2018 10:47
Last Modified: 14 Mar 2024 18:53
DOI: 10.1038/s41540-018-0058-z
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3026233