An integrated structural and functional profiling approach uncovers the mechanisms of pregnane X receptor binding and activation by pharmaceutical and environmental compounds.

Summary

Using cell-based assays and crystallography, the authors define how two approved drugs, a cosmetic flavor (sclareol), and a halogenated BPA derivative bind to and activate PXR. These ligands differentially induce PXR target genes and promote colon cancer cell proliferation, and the study delivers a reproducible pipeline for PXR ligand identification and risk evaluation.

Key Findings

• Two approved drugs, a cosmetic flavor (sclareol), and 2,2'-dichlorobisphenol A differentially bind and activate PXR.
• Ligands induced PXR target genes linked to xenobiotic metabolism and cell proliferation and variably promoted colon cancer cell growth.
• Crystallography revealed distinct binding mechanisms within the PXR ligand-binding domain.
• An integrated structural–functional pipeline was established to identify and characterize PXR ligands for risk assessment.

Clinical Implications

Highlights the need to screen cosmetic ingredients and drugs for PXR activation to mitigate drug–drug interactions, endocrine disruption, and possible tumor-promoting effects.

Limitations

• Limited number of ligands examined reduces generalizability.
• Findings are based on in vitro and structural data without in vivo validation.

Future Directions

Expand ligand libraries (including broader cosmetic ingredients), validate PXR activation signatures in vivo, and integrate computational screening to pre-emptively de-risk product development.