Glyceollin Effects on MRP2 and BCRP in Caco-2 Cells, and Implications for Metabolic and Transport Interactions

Abstract

Glyceollins are phytoalexins produced in soybeans under stressful growth conditions. Based on prior evaluations, they show potential to treat multiple diseases, including certain cancers, Type 2 diabetes and cardiovascular conditions. The aim of the present studies was to expand on recent studies designed to initially characterize the intestinal disposition of glyceollins. Specifically, studies were undertaken in Caco-2 cells to evaluate glyceollins' effects on apical efflux transporters, namely MRP2 and BCRP, which are the locus of several intestinal drug-drug and drug-food interactions. 5 (and 6)-Carboxy-2′,7′-dichloroflourescein (CDF) was used to provide a readout on MRP2 activity; whereas, BODIPY-prazosin, provided an indication of BCRP alteration. Glyceollins were shown to reverse MRP2-mediated CDF transport asymmetry in a concentration dependent manner, with activity similar to the MRP2 inhibitor, MK-571. Likewise, they demonstrated concentration dependent inhibition of BCRP-mediated efflux of BODIPY-prazosin with a potency similar to that of Ko143. Glyceollin did not appreciably alter MRP2 or BCRP expression following 24 hours of continuous exposure. The possibility that glyceollin-mediated inhibition of genistein metabolite efflux by either transporter was evaluated. However, results demonstrated an interaction at the level of glyceollin inhibition of genistein metabolism rather than inhibition of metabolite transport.

Unconjugated bilirubin elevation impairs the function and expression of breast cancer resistance protein (BCRP) at the blood-brain barrier in bile duct-ligated rats

“…The aim of the study was first to investigate whether BDL altered the expression and function of BCRP in the brains of rats by using Western blotting and assessment of the concentration of prazosin, which is a typical substrate of BCRP [30][31][32][33] , respectively, and then to identify components in BDL rat serum that affected BCRP function and expression, by using human cerebral microvessel endothelial cells (HCMEC/D3) and Madin-Darby canine kidney cells expressing human BCRP (MDCK-BCRP) as in vitro models. Additionally, the contribution of UCB to the altered function and expression of BCRP in the brain by BDL was further investigated by both in vitro and in vivo studies.…”

An Update on the Effects of Glyceollins on Human Health: Possible Anticancer Effects and Underlying Mechanisms

“…Glyceollin conjugates have also been described in vitro in CACO-2 cells [48]. In this model, glyceollins (24 h of exposure of up to 100 μM) also decreased the activity of the MRP2 and BCRP transporters (two major apically expressed efflux transporters in the intestine) without significant modification of their expression [49]. This effect can have important consequences on drug efficacy.…”

Acidity stress for the systemic elicitation of glyceollin phytoalexins in soybean plants

“…[9][10][11] Glyceollin I, in particular, inhibits the proliferation and survival of a broad range of cancer types by inhibiting ER signaling and by other unclear mechanism(s). [12][13][14][15][16][17][18][19] Conversely, glyceollins promote the survival of challenged neurons by stimulating the Nrf2/HO-1 signaling pathway. 20 The critical barriers that limit the accessibility of glyceollins are that they cannot be synthesized economically [21][22][23] or obtained in sufficient amounts from soybean tissues.…”