Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients.
ABSTRACT The transcellular transport of ingested food ingredients across the intestinal epithelial barrier is an important factor determining bioavailability upon oral intake. This transcellular transport of many chemicals, food ingredients, drugs or toxic compounds over the intestinal epithelium can be highly dependent on the activity of membrane bound ATP binding cassette (ABC) transport proteins, able to export the compounds from the intestinal cells. The present review describes the ABC transporters involved in the efflux of bioactive compounds from the intestinal cells, either to the basolateral blood side, facilitating absorption, or back into the intestinal lumen, reducing bioavailability. The role of the ABC transporters in intestinal transcellular uptake also implies a role for inhibitors of these transporters in modulation of the bioavailability upon oral uptake. The present paper focuses on the role of flavonoids as important modulators or substrates of intestinal ABC transport proteins. Several examples of such an effect of flavonoids are presented. It can be concluded that flavonoid-mediated inhibition of ABC transporters may affect the bioavailability of drugs, bioactive food ingredients and/or food-borne toxic compounds upon oral uptake. All together it appears that the flavonoid-mediated interactions at the level of the intestinal ABC transport proteins may be an important mechanism for unexpected food-drug, food-toxin or food-food interactions. The overview also indicates that future studies should focus on i) in vivo validation of the flavonoid-mediated effects on bioavailability of drugs, toxins and beneficial bioactive food ingredients detected in in vitro models, and on ii) the role of flavonoid phase II metabolism in modulating the activity of the flavonoids to act as ABC transporter inhibitors and/or substrates.
Article: Absorption of quercetin-3-glucoside and quercetin-4'-glucoside in the rat small intestine: the role of lactase phlorizin hydrolase and the sodium-dependent glucose transporter.[show abstract] [hide abstract]
ABSTRACT: Two hypotheses on absorption mechanisms of flavonoid glucosides across the small intestine have been proposed: active uptake of the quercetin glucoside by the sodium-dependent glucose transporter (SGLT1) with subsequent deglycosylation within the enterocyte by cytosolic beta-glucosidase, or luminal hydrolysis of the glucoside by lactase phlorizin hydrolase (LPH) and absorption by passive diffusion of the released aglycone. To test the above hypotheses we employed phlorizin (as an inhibitor of SGLT1) and N-(n-butyl)-deoxygalactonojirimycin (as an inhibitor of the lactase domain of LPH) in a rat everted-jejunal sac model. Quercetin-4'-glucoside mucosal hydrolysis was 10 times greater than quercetin-3-glucoside hydrolysis in the absence of inhibitors (449 and 47 nmol g(-1) tissue, respectively), despite the similar amounts (13+/-4 and 9+/-1 nmol g(-1), respectively) being transferred to the serosal compartment during the 15 min incubation. Apical hydrolysis of both quercetin glucosides was significantly reduced in the presence of NB-DGJ (80%), and transfer of quercetin (measured as quercetin metabolites) to the serosal solution was also significantly reduced (40-50%). In the presence of phlorizin, transfer of metabolites to the serosal solution was only reduced in the case of quercetin-4'-glucoside. Evidently the mechanism of absorption of quercetin-4'-glucoside involves both an interaction with SGLT1 and luminal hydrolysis by LPH, whereas quercetin-3-glucoside appears to be absorbed only following hydrolysis by LPH.Biochemical Pharmacology 05/2003; 65(7):1199-206. · 4.70 Impact Factor
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ABSTRACT: Quercetin is a dietary antioxidant that prevents oxidation of low-density lipoproteins in vitro. Intake of quercetin was inversely associated with coronary heart disease mortality in elderly Dutch men. However, the extent of absorption of quercetin in humans is unclear. The aim of this study was to quantify absorption of various forms of quercetin. Nine healthy ileostomy subjects were studied, to avoid losses caused by colonic bacteria. They followed a quercetin-free diet for 12 d; on days 4, 8, and 12 they received a supplement of fried onions at breakfast (rich in quercetin glucosides) equivalent to 89 mg aglycone, pure quercetin rutinoside (the major quercetin compound in tea) equivalent to 100 mg aglycone, or 100 mg pure quercetin aglycone, in random order. Subsequently, participants collected ileostomy effluent and urine for 13 h. In vitro incubations of quercetin or its glycosides with gastrointestinal fluids showed minimal degradation. Absorption of quercetin, defined as oral intake minus ileostomy excretion and corrected for 14% degradation within the ileostomy bag, was 52 +/- 15% for quercetin glucosides from onions, 17 +/- 15% for quercetin rutinoside, and 24 +/- 9% for quercetin aglycone. Mean excretion of quercetin or its conjugates in urine was 0.5% of the amount absorbed; quercetin excretion in urine was negatively correlated with excretion in ileostomy effluent (r = -0.78, n = 27). We conclude that humans absorb appreciable amounts of quercetin and that absorption is enhanced by conjugation with glucose.American Journal of Clinical Nutrition 01/1996; 62(6):1276-82. · 6.67 Impact Factor
Article: Quercetin-3-glucoside is transported by the glucose carrier SGLT1 across the brush border membrane of rat small intestine.[show abstract] [hide abstract]
ABSTRACT: In the present study we investigated a possible involvement of the intestinal sodium-dependent glucose transporter (SGLT)1 in the absorption of quercetin-3-glucoside (Q3G). Pieces of rat jejunum or proximal colon were mounted in Ussing-type chambers and incubated under short-circuited conditions. Test flavonols were added to the mucosal or serosal bathing solution (initial concentration, 100 micromol/L) and disappearance from the donor compartment was monitored for 2 h. With jejunal tissue, only 13.6 +/- 3.5% of the initial dose of Q3G was found in the mucosal compartment 2 h after mucosal addition. Simultaneous addition of D-glucose (10 mmol/L) significantly reduced the disappearance of Q3G (remaining concentration, 33.4 +/- 6.9%) as did a Na(+)-free buffer solution containing phloridzin (final mucosal concentration of Q3G, 54.2 +/- 7.7%). In these experiments, disappearance of Q3G was paralleled by the appearance of quercetin in the mucosal solutions. In contrast, D-fructose (10 mmol/L) did not influence the disappearance of Q3G (Na(+)-free conditions). With proximal colon, 78.2 +/- 11.5% of the initial concentration of Q3G was still present in the mucosal solution after 2 h. When added to the serosal side, the concentration of Q3G decreased only slightly (jejunum, 96.1 +/- 2.1%; proximal colon, 90.7 +/- 1.2%). The concentration of rutin did not change after mucosal or serosal addition. Neither transport of intact glycosides nor of free quercetin from the donor into the acceptor compartment was observed under our experimental conditions. Taken together, the results clearly indicate a role of SGLT1 in mucosal uptake of the Q3G.Journal of Nutrition 05/2002; 132(4):630-5. · 3.92 Impact Factor