Collaborative SAR Modeling and Prospective In Vitro Validation of Oxidative Stress Activation in Human HepG2 Cells

Area of Science:

• Biochemistry
• Toxicology
• Cell Biology

Background:

• Oxidative stress arises from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses.
• Xenobiotics can exacerbate oxidative stress by interfering with redox processes and diminishing antioxidant capacity.
• Severe oxidative stress can lead to cellular damage when detoxification mechanisms are overwhelmed.

Purpose of the Study:

• To develop predictive structure-activity relationship (SAR) models for cellular antioxidant responses.
• To assess the impact of a large library of drug and drug-like compounds on oxidative stress.
• To validate the predictive power of developed SAR models against experimental data.

Main Methods:

• Utilized a reporter system (Srxn1-GFP) to quantify the antioxidant response in HepG2 cells.
• Screened 2230 compounds to classify their effect on cellular oxidative stress.
• Developed and applied SAR models to predict compound-induced oxidative stress.

Main Results:

• Successfully classified compounds based on their ability to induce or not induce oxidative stress.
• Established SAR models demonstrating relationships between chemical structures and antioxidant responses.
• Validated model predictions with a new set of compounds, confirming predictive accuracy.

Conclusions:

• Demonstrates the feasibility of developing SAR models for phenotypic cellular readouts like oxidative stress.
• Highlights challenges in model development, including chemical space selection and data interpretation.
• Provides a framework for predicting compound-induced oxidative stress, contributing to drug safety and discovery.