Potentin vitroInhibition of CYP3A4 and P-Glycoprotein byRhodiola rosea

Abstract

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.

In vitro inhibition of cytochrome P-450 activities and quantification of constituents in a selection of commercial Rhodiola rosea products

“…In our study, the concentration of each measured R. rosea constituent could not be correlated to the enzyme inhibition and are not likely responsible for the observed effect, further fortified by the fact that Nuodikang did not differ significantly in inhibitory potential despite not containing any rosavins. Our study confirms the findings of Hellum et al (2010) and adds to the evidence that the bioactive constituents rosavin, rosarin, rosin, salidroside and tyrosol of R. rosea does not seem to inhibit CYP3A4, 2D6 or 1A2. Further studies on isolated constituents of R. rosea are needed to identify the constituents responsible.…”

“…Hellum et al (2010) showed that ethanol extracts of R. rosea clones (raw plant material) significantly inhibited CYP3A4 in vitro, with IC 50 values ranging from 1.7-3.1 lg/mL. An in vitro inhibition was also shown by Scott et al (2006), where 220 lg/mL ethanol extracts inhibited CYP3A4 activity by 49 ± 15% and CYP19 (aromatase) activity by 69 ± 7% as compared with control.…”

“…Two studies have been published evaluating R. rosea constituents and in vitro CYP enzyme inhibition. Hellum et al (2010) examined if the concentration of the supposed bioactive constituents of R. rosea, rosavin, rosarin, rosin, salidroside and tyrosol, could be correlated to CYP3A4 inhibition, but found no such correlation (Hellum et al 2010). In a more recent study, Xu et al (2013) evaluated the inhibition of CYP2D6 by eight of the less recognized R. rosea constituents and found a potent inhibition by the constituents rhodiosin and rhodionin on CYP2D6 enzyme activity with IC 50 values of 0.761 lM (0.47 lg/mL) and 0.42 lM (0.19 lg/mL), respectively (Xu et al 2013).…”

“…Rhodiola rosea constituents: the concentration of extracted rosavin, rosin, rosarin, salidroside and tyrosol, in the different R. rosea extracts were determined in a solution of 100 lg R. rosea crude extract/mL of extraction solution by a validated HPLC methodology described earlier (Hellum et al 2010), with some modifications. Using an Agilent 1200 HPLC system the constituents were separated with a Zorbax Eclipse XDB C18 column (5 lm, 150 mm Â4.6 mm), connected after a Zorbax SB-C18 guard column (5 lm, 12.5 mm  4.6 mm), at 30 C. UV detection at 250 nm was used for rosavin, rosin and rosarin, while salidroside and tyrosol were detected at 210 nm.…”

“…Five studies have previously been published on CYP inhibition by full extracts of R. rosea (Scott et al 2006;Panossian et al 2009;Hellum et al 2010;Spanakis et al 2013;Thu et al 2016). Hellum et al (2010) showed that ethanol extracts of R. rosea clones (raw plant material) significantly inhibited CYP3A4 in vitro, with IC 50 values ranging from 1.7-3.1 lg/mL.…”