Potent in vitro inhibition of CYP3A4 and P-glycoprotein by Rhodiola rosea.
Six clones of RHODIOLA ROSEA, obtained from plants originating from widely different areas in Norway, were investigated for their IN VITRO inhibitory potential on CYP3A4-mediated metabolism and P-gp efflux transport activity. Presumed active constituents in the ethanol extracts of the different clones were quantified. C-DNA baculovirus expressed CYP3A4 and Caco-2 cells were used for inhibitory assays, and as positive control inhibitors ketoconazole and verapamil were applied, respectively. A validated HPLC methodology was used to quantify the formation of 6-beta-OH-testosterone and scintillation counting was used to quantify the transport of (3)H-digoxin in Caco-2 cells. All clones showed potent inhibition of CYP3A4 and P-gp activities, with IC (50) values ranging from 1.7 to 3.1 microg/mL and from 16.7 to 51.7 microg/mL, respectively, being below that reported for other herbs and some known classic drug inhibitors, such as St. John's wort and fluoxetine. RHODIOLA ROSEA might thus be a candidate for clinically relevant drug interactions. The concentration of presumed biologically active constituents in the different clones varied considerably, but this variation was not related to the clones' inhibitory potential on CYP3A4 or P-gp activities. Other constituents might thus be responsible for the observed inhibitory properties. The place of origin seemed to be of minor importance for CYP3A4 or P-gp inhibition.
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. bent.h.hellum@ntnu.no
Bent H
BH
Hellum
Anita
A
Tosse
Kathrine
K
Hoybakk
Mette
M
Thomsen
Jens
J
Rohloff
Odd
O
Georg Nilsen
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D016367:Baculoviridae; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D018076:DNA, Complementary; D004077:Digoxin / Q000378:metabolism; D041743:Herb-Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000494:pharmacology; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D029771:Rhodiola / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065692:Cytochrome P-450 CYP3A Inhibitors; D018076:DNA, Complementary; D010936:Plant Extracts; D013739:Testosterone; D004077:Digoxin; D014700:Verapamil; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole