Berry anthocyanins and anthocyanidins exhibit distinct affinities for the efflux transporters BCRP and MDR1

Abstract

Background and purpose: Dietary anthocyanins hold great promise in the prevention of chronic disease but factors affecting their bioavailability remain poorly defined. Specifically, the role played by transport mechanisms at the intestinal and blood-brain barriers (BBB) is currently unknown. Experimental approach: In the present study, 16 anthocyanins and anthocyanidins were exposed to the human efflux transporters multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), using dye efflux, ATPase and, for BCRP, vesicular transport assays. Key results: All test compounds interacted with the BCRP transporter in vitro. Of these, seven emerged as potential BCRP substrates (malvidin, petunidin, malvidin-3-galactoside, malvidin-3,5-diglucoside, cyanidin-3-galactoside, peonidin-3-glucoside, cyanidin-3-glucoside) and 12 as potential inhibitors of BCRP (cyanidin, peonidin, cyanidin-3,5-diglucoside, malvidin, pelargonidin, delphinidin, petunidin, delphinidin-3-glucoside, cyanidin-3-rutinoside, malvidin-3-glucoside, pelargonidin-3,5-diglucoside, malvidin-3-galactoside). Malvidin, malvidin-3-galactoside and petunidin exhibited bimodal activities serving as BCRP substrates at low concentrations and, at higher concentrations, as BCRP inhibitors. Effects on MDR1, in contrast, were weak. Only aglycones exerted mild inhibitory activity. Conclusions and implications:Although the anthocyanidins under study may alter pharmacokinetics of drugs that are BCRP substrates, they are less likely to interfere with activities of MDR1 substrates. The present data suggest that several anthocyanins and anthocyanidins may be actively transported out of intestinal tissues and endothelia, limiting their bioavailability in plasma and brain.

Cytocidal Effects of Polyphenolic Compounds, Alone or in Combination with, Anticancer Drugs Against Cancer Cells: Potential Future Application of the Combinatory Therapy

“…It is worthy of note that flavonoids have been revealed to inhibit the function of ATP-binding cassette transporters such as multidrug resistance-associated proteins as well as P-glycoprotein [90], similar to our recent study [91]. On the other hand, a recent study demonstrated that berry anthocyanins, such as cyanidin-3-galactosidee, and cyanidin-3-glucoside as well as peonidin-3-glucosid, exhibit affinities for the efflux transporters breast cancer resistance protein (BCRP) and consequently may be actively transported out of intestinal tissues and endothelia [92]. However, the same report also demonstrated that some berry anthocyanins and anthocyanidins, such as delphinidin, cyanidin and cyanidin-3-rutinoside, act as BCRP inhibitor, while some of them, such as malvidin, malvidin-3-galactoside and petunidin, exhibited bimodal activities serving as BCRP substrates and inhibitors at low concentrations and high concentrations, respectively [92].…”

“…On the other hand, a recent study demonstrated that berry anthocyanins, such as cyanidin-3-galactosidee, and cyanidin-3-glucoside as well as peonidin-3-glucosid, exhibit affinities for the efflux transporters breast cancer resistance protein (BCRP) and consequently may be actively transported out of intestinal tissues and endothelia [92]. However, the same report also demonstrated that some berry anthocyanins and anthocyanidins, such as delphinidin, cyanidin and cyanidin-3-rutinoside, act as BCRP inhibitor, while some of them, such as malvidin, malvidin-3-galactoside and petunidin, exhibited bimodal activities serving as BCRP substrates and inhibitors at low concentrations and high concentrations, respectively [92]. These findings suggest that a variety of biological activities of anthocyanins and anthocyanidins may be attributed in part to their inhibitory effects on those drug transporters, paradoxically, may be abolished as a result of efflux through those transporters.…”

Dietary Anthocyanins: Impact on Colorectal Cancer and Mechanisms of Action

“…Moreover, a different behavior depending on the molecular structure was also demonstrated. Dreiseitel and colleagues showed that, depending on the sugar moiety, some flavonoids can act as BCRP stimulators while others act as inhibitors (Dreiseitel et al, 2009;Morris and Zhang, 2006). However, the significance of these flavonoid-efflux transporter interactions has not been unequivocally demonstrated since it is impossible to exclude the involvement of other drugs transporters and of intracellular metabolizing enzymes that modify the substrate disposition (Morris and Zhang, 2006).…”

“…Felgines and colleagues administered an oral dose of a radiolabelled cyanidin 3-O-glucoside, demonstrating that the major site of absorption in mice is the intestine with a minimal accumulation of the radioactivity in tissues out of the gastrointestinal tract (Felgines et al, 2010). Intestinal barrier is impermeable to most flavonoid glucosides because, based on their molecular structure, anthocyanins and their aglycones cannot cross the cell membrane passively (Dreiseitel et al, 2009). Among the influx carriers, the hexose transporters SGLT1 and GLUT 5 are expressed on apical membrane of the intestinal epithelium.…”

Oral Bioavailability and Disposition of Phytochemicals

“…Knocking out mouse Bcrp led to significant increases in the oral bioavailability of daidzen (3.7-fold) and genistein (1.8-fold) compared to wild type mice (Enokizono et al, 2007). Several flavonoids such as quercetin, kaempferol, and diverse anthocyanins and anthocyanidins commonly found in grapes and berries, malvidin, petunidin, malvidin-3-galactoside, malvidin-3,5-diglucoside, cyanidin-3-galactoside, peonidin-3-glucoside and cyanidin-3-glucoside have also been identified as BCRP substrates (Dreiseitel et al, 2009;An et al, 2010). Thus BCRP may limit the absorption of these PCs, but to date, human pharmacokinetic data are not available to confirm this.…”