Xenobiotic receptor humanized mice and their utility

Area of Science:

• Pharmacology and Toxicology
• Molecular Biology
• Drug Discovery

Background:

• Nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), and peroxisome proliferator-activated receptor alpha (PPARα) regulate drug metabolism.
• Aryl hydrocarbon receptor (AhR) also influences xenobiotic responses, functionally overlapping with PXR, CAR, and PPARα.
• Significant species differences exist in receptor activation and biological outcomes, limiting the translatability of preclinical data.

Purpose of the Study:

• To review existing xenobiotic receptor humanized mouse models.
• To summarize the application of these models in basic research and drug development.
• To highlight their utility in predicting human responses to xenobiotics.

Main Methods:

• Review of literature on xenobiotic receptor humanized mouse models.
• Description of model creation and characterization.
• Discussion of applications in drug induction, drug-drug interactions, toxicity, and efficacy studies.

Main Results:

• Various humanized mouse models for PXR, CAR, PPARα, and AhR have been developed.
• These models demonstrate species-specific responses, enhancing predictive value for humans.
• Applications include evaluating drug metabolism, interactions, carcinogenicity, and efficacy.

Conclusions:

• Humanized mouse models are valuable tools for overcoming species differences in xenobiotic receptor research.
• They significantly improve the prediction of human responses, aiding drug discovery and development.
• Careful interpretation and future development of these models are crucial for maximizing their utility.