SGLT-1 Transport and Deglycosylation inside Intestinal Cells Are Key Steps in the Absorption and Disposition of Calycosin-7-O- -D-Glucoside in Rats

Abstract

Hydrolysis by lactase-phloridzin hydrolase (LPH) is the first and critical step in the absorption of isoflavonoid glucosides. However, the absorption characteristics of calycosin-7-O-b-D-glucoside (CG) slightly differ from other isoflavonoid glucosides. In this study, we used the rat intestinal perfusion model and performed pharmacokinetic studies and in vitro experiments to determine the factors influencing CG absorption and disposition. After oral administration of isoflavonoid glucosides, LPH was found to play minimal or no role on the hydrolysis of CG, in contrast to that of daidzin. CG was mainly transported into the small intestinal cells by sodium-dependent glucose transporter 1 (SGLT-1) as intact. This pathway could be the main mechanism underlying the high permeability of CG in the small intestine. CG was likely to be hydrolyzed in enterocytes to its aglycone calycosin by broad-specific b-glucuronides (BSbG) and glucocerebrosidase or rapidly metabolized. Calycosin was also rapidly and extensively metabolized to 39-glucuronide in the enterocytes and liver, and the glucuronidation rates of calycosin and CG were much higher in the former. The metabolites were also transported into lumen by breast cancer resistance protein and multidrug resistance-associated protein 2. In conclusion, the enterocytes could be an important site for CG absorption, deglycosylation, and metabolism in rats. This study could contribute to the theoretical foundation and mechanism of absorption and disposition of flavonoid compounds.

Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Determine the Disposition of Esculetin-7-O-Glucuronide and 4-Methylesculetin-7-O-Glucuronide

“…route to thoroughly evaluate the disposition of the ET-G and 4-ME-G will also be conducted. Although the inhibition specificity of Ko143 and MK571 has been debated frequently, they are commonly used in screening BCRP and MRP2 substrates in in vitro assays (Sheng et al, 2015;Shi et al, 2016). These results of the inhibition assay were consistent with previous findings in which most glucuronides are substrates of BCRP and MRP2 (An and Morris, 2011;Zheng et al, 2016).…”

“…Inhibition assays in Caco-2 monolayers are also commonly used to identify transporter substrates. Ko143 (at concentrations from 0.5 to 10 mM) and MK571 (at concentrations from 10 to 100 mM) are frequently used to confirm the role of BCRP and MRPs [including MRP2 expressed on the AP membrane and MRP3 and MRP4 expressed on the basolateral (BL) membrane] in the disposition of xenobiotics in previous studies (Sheng et al, 2015;Shi et al, 2016;Ma et al, 2017;Zang et al, 2018).…”

Flavonoid metabolism: the interaction of metabolites and gut microbiota

“…Hydrolysis of isoflavone glucosides is mainly carried out by CBG in the cell-free extract of human intestine and liver, with a lesser contribution of LPH than in rats [20]. Recently, calycosin-7-O-glucoside, a methylated isoflavone, was reported to be a novel substrate for SGLT1 but not for LPH in rats [21]. Thus, deglycosylation in the small intestine may be important to increase the bioavailability of flavonoid monoglucosides, although performance of the subsequent step by the microbiota may be sufficient to compensate for the absence of this process.…”

Citrus Flavones: An Update on Sources, Biological Functions, and Health Promoting Properties

“…Some flavonoids such as quercetin are transported into the cells by passive diffusion [40]. Moreover, although the sodium-dependent glucose transporter 1 is involved in the uptake of some flavonoid glycosides such as quercetin 3-O-glucoside [41], it seems that this mechanism is not involved in the transport of flavones because some of them, such as luteolin, specifically inhibit this transporter [42]. In light of this, the transport of less polar molecules (e.g., aglycone) across the lipid membrane, seems to be favored [41].…”

“…Moreover, although the sodium-dependent glucose transporter 1 is involved in the uptake of some flavonoid glycosides such as quercetin 3-O-glucoside [41], it seems that this mechanism is not involved in the transport of flavones because some of them, such as luteolin, specifically inhibit this transporter [42]. In light of this, the transport of less polar molecules (e.g., aglycone) across the lipid membrane, seems to be favored [41]. In light of this, it is clear that flavones O-glycosides must be hydrolyzed to the respective aglycons before absorption in the small intestine epithelial cells can take place and, therefore, CBG being a cytosolic enzyme, it does not play a role in their deglycosylation.…”