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

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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.

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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

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ACKNOWLEDGEMENTS

This study was supported by a Schlieben-Lange-Grant from the Ministry of Science, Research and the Arts Baden-Württemberg and the European Social Fund (to M.O.) and by a German Research Foundation grant GF1211/9-1 (to G.F.).

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Authors and Affiliations

  1. Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University Heidelberg, INF 366, 69120, Heidelberg, Germany

    Melanie Ott & Gert Fricker

  2. Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB, Nijmegen, The Netherlands

    Miriam Huls

  3. Department of Biosciences and Nutrition, Karolinska Institutet, 141 57, Huddinge, Sweden

    Michael G. Cornelius

Authors
  1. Melanie Ott
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  2. Miriam Huls
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  4. Gert Fricker
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Correspondence to Gert Fricker.

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Ott, M., Huls, M., Cornelius, M.G. et al. St. John’s Wort Constituents Modulate P-glycoprotein Transport Activity at the Blood-Brain Barrier. Pharm Res 27, 811–822 (2010). https://doi.org/10.1007/s11095-010-0074-1

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  • DOI: https://doi.org/10.1007/s11095-010-0074-1

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