Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

Area of Science:

• Pharmacology and Toxicology
• Computational Biology
• Systems Biology

Background:

• Drug-induced liver injury (DILI) presents a significant challenge in drug development due to its unpredictable nature.
• Hepatic adaptive stress response pathways are consistently activated during DILI.
• Current methods, including animal trials, often fail to predict DILI accurately.

Purpose of the Study:

• To review the progress in dynamical modeling of stress and death pathways relevant to DILI.
• To explore the application of ordinary differential equation (ODE) modeling for understanding DILI mechanisms.
• To discuss the adaptation of existing pathway models for DILI research.

Main Methods:

• Review of existing literature on dynamical modeling of cellular stress pathways.
• Analysis of ODE models for pathways including oxidative stress, inflammation, DNA damage, unfolded proteins, heat shock, and apoptosis.
• Discussion on the requirements for applying these models to liver-specific DILI prediction.

Main Results:

• Significant advancements have been made in modeling cellular stress pathways since 2000.
• Models of stress pathways have been rarely applied specifically to DILI dynamics.
• Existing models can often be repurposed for DILI research with parameter adjustments.

Conclusions:

• Dynamical pathway modeling holds potential for predicting adverse drug effects before clinical trials.
• Repurposing existing stress pathway models can accelerate DILI research.
• Integrating dynamical models with in vitro testing may yield novel screening methods for drug-induced toxicity.