Mathematical modelling reveals compound-specific stress pathway activity

Area of Science:

• Toxicology
• Computational Biology
• Pharmacology

Background:

• Drug-induced liver injury (DILI) poses significant challenges in pharmaceutical development.
• Cellular stress pathway activation is a key indicator of potential DILI.
• Understanding these pathways is crucial for predicting drug toxicity.

Purpose of the Study:

• To develop a mathematical model simulating cellular stress responses to DILI-inducing compounds.
• To investigate the stress responses invoked by nitrofurantoin, diclofenac, and ketoconazole.
• To analyze the differences in transcription factor interactions within conserved stress pathways.

Main Methods:

• Utilized imaging data from HepG2 cells.
• Measured cell-associated compound levels and intracellular glutathione.
• Developed and recalibrated a mathematical model for integrated and oxidative stress responses.

Main Results:

• A mathematical model was successfully developed and applied to three DILI-liable compounds.
• Model parameters required recalibration for different compounds, but the core structure remained consistent.
• Analysis revealed varying magnitudes of transcription factor interactions despite activation of similar pathways.

Conclusions:

• The developed mathematical model provides a framework for understanding DILI mechanisms.
• Cellular stress responses to DILI compounds can be quantitatively modeled.
• Differences in pathway interaction magnitudes highlight compound-specific toxicity profiles.