Probing Ligand Structure–Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8-Hydroxyefavirenz Exhibit Divergence in Activation

Bhargavi Narayanan, Julie M. Lade, Carley J.S. Heck, Kevin D. Dietz, Herschel Wade, Namandjé N. Bumpus

Research output: Contribution to journalArticlepeer-review

Abstract

Efavirenz (EFV), an antiretroviral that interacts clinically with co-administered drugs via activation of the pregnane X receptor (PXR), is extensively metabolized by the cytochromes P450. We tested whether its primary metabolite, 8-hydroxyEFV (8-OHEFV) can activate PXR and potentially contribute to PXR-mediated drug–drug interactions attributed to EFV. Luciferase reporter assays revealed that despite only differing from EFV by an oxygen atom, 8-OHEFV does not activate PXR. Corroborating this, treatment with EFV for 72 h elevated the mRNA abundance of the PXR target gene, Cyp3a11, by approximately 28-fold in primary hepatocytes isolated from PXR-humanized mice, whereas treatment with 8-OHEFV did not result in a change in Cyp3A11 mRNA levels. FRET-based competitive binding assays and isothermal calorimetry demonstrated that even with the lack of ability to activate PXR, 8-OHEFV displays an affinity for PXR (IC 50 12.1 μm; K D 7.9 μm) nearly identical to that of EFV (IC 50 18.7 μm; K D 12.5 μm). The use of 16 EFV analogues suggest that other discreet changes to the EFV structure beyond the 8-position are well tolerated. Molecular docking simulations implicate an 8-OHEFV binding mode that may underlie its divergence in PXR activation from EFV.

Original languageEnglish (US)
Pages (from-to)736-747
Number of pages12
JournalChemMedChem
Volume13
Issue number7
DOIs
StatePublished - Apr 6 2018

Keywords

  • cytochrome P450
  • drug metabolism
  • ligand binding
  • molecular docking
  • nuclear receptors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Probing Ligand Structure–Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8-Hydroxyefavirenz Exhibit Divergence in Activation'. Together they form a unique fingerprint.

Cite this