Metabolism and Transport of the Citrus Flavonoid Hesperetin in Caco-2 Cell Monolayers

Abstract

ABSTRACT:Metabolism and transport from intestinal cells back into the lumen by ATP-binding cassette (ABC) transporters is believed to limit the bioavailability of flavonoids. We studied metabolism and transport of the citrus flavonoid hesperetin, the aglycone of hesperidin, using a two-compartment transwell Caco-2 cell monolayer system, simulating the intestinal barrier. The role of apically located ABC (3.7) and 2.1 (0.8) pmol/min/monolayer, respectively. Hesperetin aglycone also permeated to the basolateral side, and this process was unaffected by the inhibitors used, possibly implying a passive diffusion process. Inhibition studies, however, showed that efflux of hesperetin conjugates to the apical side involved active transport, which from the pattern of inhibition appeared to involve mainly BCRP. Upon inhibition by the BCRP inhibitor Ko143 (5 M), the apical efflux of hesperetin conjugates was 1.9-fold reduced (p < 0.01), and transport to the basolateral side was 3.1-fold increased (p < 0.001). These findings elucidate a novel pathway of hesperetin metabolism and transport and show that BCRPmediated transport could be a limiting step for hesperetin bioavailability.

Chrysin blocks topotecan-induced apoptosis in Caco-2 cells in spite of inhibition of ABC-transporters

“…Another possible mechanism for flavonoid-mediated inhibition of ABC-transporters is by competitive inhibition when flavonoids act as substrates [10,13]. Whereas the free aglycones appear to be mainly transported by P-gp, intracellularly formed glucuronidated and sulfated conjugates can be transported by MRP-2 and BCRP [10,14,15].…”

Arylsulfatase B Mediates the Sulfonation-Transport Interplay in Human Embryonic Kidney 293 Cells Overexpressing Sulfotransferase 1A3

“…Hesperetin is extensively metabolized by phase II enzymes to form sulfate and glucuronide conjugates, resulting in exceedingly low bioavailability after oral administration (Brand et al, 2008(Brand et al, , 2010. Recent studies have indicated that phase II conjugates of hesperetin retain the biologic activities of the parent molecule (Takumi et al, 2012;Yang et al, 2012).…”

Determination of Subcellular Localization of Flavonol in Cultured Cells by Laser Scanning

“…To elucidate these points, further study is needed to clarify the structure-fluorescence relationship and absorption mechanism in cultured cells. Cellular efflux is also an important event in flavonol metabolism, and flavonols are known to be excreted from cells through a cell membrane efflux transporter (Brand, et al 2008;Ofer, et al 2005). Treatment of cells with an inhibitor of the efflux pump such as Pglycoprotein increases the cellular concentration of flavonol and enhances its beneficial effects in cultured cells and experimental animals (Mukai, et al 2009a;Wang, et al 2005).…”