Saint John's wort: an in vitro analysis of P-glycoprotein induction due to extended exposure

Br J Pharmacol. 2001 Dec;134(8):1601-8. doi: 10.1038/sj.bjp.0704399.

Abstract

1. Chronic use of Saint John's wort (SJW) has been shown to lower the bioavailability for a variety of co-administered drugs including indinavir, cyclosporin, and digoxin. Decreases in intestinal absorption through induction of the multidrug resistance transporter, P-glycoprotein (P-gp), may explain decreased bioavailability. 2. The present study characterized the response of P-gp to chronic and acute exposure of SJW and hypericin (HYP, a presumed active moiety within SJW) in an in vitro system. Experiments were performed with 3 to 300 microg ml(-1) of methanol-extracted SJW and 0.03 to 3 microM HYP, representing low to high estimates of intestinal concentrations. 3. In induction experiments, LS-180 intestinal carcinoma cells were exposed for 3 days to SJW, HYP, vehicle or a positive control (ritonavir). P-gp was quantified using Western blot analysis. P-gp expression was strongly induced by SJW (400% increase at 300 microg ml(-1)) and by HYP (700% at 3 microM) in a dose-dependent fashion. Cells chronically treated with SJW had decreased accumulation of rhodamine 123, a P-gp substrate, that was reversed with acute verapamil, a P-gp inhibitor. Fluorescence microscopy of intact cells validated these findings. In Caco-2 cell monolayers, SJW and HYP caused moderate inhibition of P-gp-attributed transport at the maximum concentrations tested. 4. SJW and HYP significantly induced P-gp expression at low, clinically relevant concentrations. Similar effects occurring in vivo may explain the decreased bioavailability of P-gp substrate drugs when co-administered with SJW.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacology
  • Biological Transport, Active / drug effects
  • Blotting, Western
  • Caco-2 Cells
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Resistance, Multiple
  • Humans
  • Hypericum* / metabolism
  • Image Processing, Computer-Assisted
  • Microscopy, Fluorescence
  • Perylene / administration & dosage
  • Perylene / analogs & derivatives*
  • Perylene / pharmacology
  • Protein Kinase C / antagonists & inhibitors
  • Rhodamine 123 / metabolism
  • Ritonavir / pharmacology
  • Time Factors
  • Tumor Cells, Cultured
  • Verapamil / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antidepressive Agents
  • Rhodamine 123
  • Perylene
  • hypericin
  • Verapamil
  • Protein Kinase C
  • Ritonavir