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Title: Echinacea sanguinea and Echinacea pallida extracts stimulate glucuronidation and basolateral transfer of Bauer alkamids 8 and 10 and ketone 24 and inhibit p-glycoprotein transporter in Caco-2 cells

Author
item QIANG, ZHIYI - Iowa State University
item HAUCK, CATHY - Iowa State University
item MCCOY, JOE-ANN - Bent Creek Institute
item Widrlechner, Mark
item REDDY, MANJU - Iowa State University
item MURPHY, PATRICIA - Iowa State University
item HENDRICH, SUZANNE - Iowa State University

Submitted to: Planta Medica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/9/2013
Publication Date: 2/15/2013
Citation: Qiang, Z., Hauck, C., McCoy, J., Widrlechner, M.P., Reddy, M.B., Murphy, P.A., Hendrich, S. 2013. Echinacea sanguinea and Echinacea pallida extracts stimulate glucuronidation and basolateral transfer of Bauer alkamids 8 and 10 and ketone 24 and inhibit p-glycoprotein transporter in Caco-2 cells. Planta Medica. 79(03/04):266-274.

Interpretive Summary: Echinacea is widely used as a medicinal herb in the US, and many studies have assessed its effectiveness in modulating human immune systems. How well Echinacea works depends on how well its bioactive components are taken from the intestine and into our blood. We examined four components, Bauer alkamides 8, 10 and 11 and ketone 24, and proposed that they would be absorbed similarly either as pure compounds or from complex ethanol extracts made from E. sanguinea and E. pallida. We also wanted to know if Echinacea extracts could inhibit P-glycoprotein transporter (P-gp) in a line of human intestinal epithelial cells called Caco-2. We were able to determine that alkamide permeation by passive diffusion across Caco-2 cells corresponded with the degree these compounds dissolved into water, independent of other extract components. Both extracts stimulated Caco-2 cells to modify alkamides 8 and 10 and for the modified compounds to then leave the cells. Bauer ketone 24 was metabolized to a more soluble form both when administered in pure form and when present in the extracts. Bauer alkamides 8, 10 and 11 and ethanol extracts of E. sanguinea and E. pallida decreased the outflow of the P-gp probe, calcein-AM, from Caco-2 cells. Our results suggest that other constituents in these extracts facilitated the metabolism and outflow of alkamides and ketones, which might improve their therapeutic benefits. Medical and pharmacological researchers should investigate whether these alkamides and Echinacea extracts would be useful in activating therapeutic agents which serve substrates for P-gp.

Technical Abstract: The use of Echinacea as a medicinal herb is prominent in the United States, and many studies have assessed the effectiveness of Echinacea as an immunomodulator. We hypothesized that Bauer alkamides 8, 10 and 11 and ketone 24 were absorbed similarly either as pure compounds or from Echinacea sanguinea and Echinacea pallida ethanol extracts, as well as that these Echinacea extracts could inhibit P-glycoprotein transporter (P-gp) in Caco-2 human intestinal epithelial cells. Using HPLC analysis, the permeation rate of Bauer alkamides by passive diffusion across Caco-2 cells corresponded with compound hydrophilicity (alkamide 8 > 10 > 11), independent of the plant extract matrix. Both Echinacea ethanol extracts stimulated apparent glucuronidation and basolateral efflux of glucuronides of alkamides 8 and 10 but not alkamide 11. Bauer ketone 24 was totally metabolized to more hydrophilic metabolites when administered as a single compound, but was glucuronidated when present in Echinacea extracts. Bauer alkamides 8, 10 and 11 (175-230 µM) and ethanol extracts of E. sanguinea (1 mg/mL, containing ~90 µM total alkamides) and E. pallida (5 mg/mL, containing 285 µM total alkamides) decreased the efflux of the P-gp probe calcein-AM from Caco-2 cells. These results suggest that other constituents in these Echinacea extracts facilitated the metabolism and efflux of alkamides and ketones, which might improve therapeutic benefits. Alkamides and Echinacea extracts might be useful in potentiating some chemotherapeutics which are substrates for P-gp.