Pharmaceutical Research

, Volume 27, Issue 5, pp 811–822

St. John’s Wort Constituents Modulate P-glycoprotein Transport Activity at the Blood-Brain Barrier

Authors

  • Melanie Ott
    • Institute of Pharmacy and Molecular BiotechnologyRuprecht-Karls-University Heidelberg
  • Miriam Huls
    • Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life SciencesRadboud University Nijmegen Medical Centre
  • Michael G. Cornelius
    • Department of Biosciences and NutritionKarolinska Institutet
    • Institute of Pharmacy and Molecular BiotechnologyRuprecht-Karls-University Heidelberg
Research Paper

DOI: 10.1007/s11095-010-0074-1

Cite this article as:
Ott, M., Huls, M., Cornelius, M.G. et al. Pharm Res (2010) 27: 811. doi:10.1007/s11095-010-0074-1

Abstract

Purpose

The purpose of this study was to investigate the short-term signaling effects of St. John’s Wort (SJW) extract and selected SJW constituents on the blood-brain barrier transporter P-glycoprotein and to describe the role of PKC in the signaling.

Methods

Cultured porcine brain capillary endothelial cells (PBCEC) and freshly isolated brain capillaries from pig were used as in vitro/ex vivo blood-brain barrier model. SJW modulation of P-glycoprotein function was studied in PBCEC using a calcein-AM uptake assay and in isolated pig brain capillaries using the fluorescent cyclosporine A derivative NBD-CSA and confocal microscopy.

Results

SJW extract and the constituents hyperforin, hypericin, and quercetin decreased P-glycoprotein transport activity in a dose- and time-dependent manner. SJW extract and hyperforin directly inhibited P-glycoprotein activity, whereas hypericin and quercetin modulated transporter function through a mechanism involving protein kinase C. Quercetin at high concentrations decreased P-glycoprotein transport activity, but increased transporter function at low concentrations. This increase in P-glycoprotein activity was likely due to trafficking and membrane insertion of vesicles containing transporter protein.

Conclusions

Our findings provide new insights into the short-term interaction of SJW with P-glycoprotein at the blood-brain barrier. They are of potential relevance given the wide use of SJW as OTC medication and the importance P-glycoprotein has for CNS therapy.

KEY WORDS

blood-brain barrierP-glycoproteinprotein kinase CregulationSt. John’s wort

ABBREVIATIONS

HC

Hypericin

HF

Hyperforin

PBCEC

Porcine brain capillary endothelial cells

PKC

Protein kinase C

PMA

Phorbol 12-myristate 13-acetate

PXR

Pregnane X receptor

QE

Quercetin

SJW

St. John’s wort

Supplementary material

11095_2010_74_MOESM1_ESM.pdf (18 kb)
ESM1Supplemental Data (PDF 17 kb)

Copyright information

© Springer Science+Business Media, LLC 2010