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SHORT COMMUNICATION

THE ß-D-GLUCOSIDE AND SODIUM-DEPENDENT GLUCOSE TRANSPORTER 1 (SGLT1)-INHIBITOR PHLORIDZIN IS TRANSPORTED BY BOTH SGLT1 AND MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS 1/2

	Abstract

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Phloridzin, a glucoside of the flavonoid-like polyphenol phloretin, has long been known to be a specific nontransportable inhibitor of the sodium-dependent glucose transporter SGLT1. The objective of this study was to determine whether efflux by multidrug resistance-associated protein (MRP) transporters might have masked the absorption by SGLT1 in previous studies. Various cells used as transport models were incubated with phloridzin (50 µM) in the absence and presence of 50 µM 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK-571), a highly selective MRP1/MRP2 inhibitor, and the cellular uptake of phloridzin was measured by high performance liquid chromatography. The uptake of phloridzin by SGLT1-transfected Chinese hamster ovary (CHO) (G6D3) cells was 1.7-fold higher than that by parent CHO cells (p < 0.01). In the presence of MK-571, the uptake of phloridzin by CHO cells increased 3.7-fold (p < 0.001). MK-571 caused an 8.0-fold increase in the uptake of phloridzin by G6D3 cells (p < 0.0001). Thus, in the absence of MRP1 efflux, transport of phloridzin by SGLT1 was clearly demonstrated. Similar results were obtained for the glycosides of the flavonoids quercetin, genistein, and diosmetin. A significantly lower accumulation of phloridzin in MRP2-transfected Madin-Darby canine kidney (MDCK) cells compared with parent MDCK cells demonstrated that phloridzin was a substrate also for MRP2 (p < 0.05). This conclusion was further strengthened when MK-571 increased the uptake by MRP2-MDCK cells as much as 3.6-fold (p < 0.01). These results demonstrate that phloridzin, in contrast to previous notions, is transported by SGLT1. In addition, they demonstrate that this and other flavonoid glycosides unexpectedly are efficiently effluxed by both MRP1 and MRP2.

View larger version (15K): [in this window] [in a new window]   FIG. 1. Chemical structures of phloridzin and its deglycosylated metabolite phloretin.

To test this postulate, we examined the accumulation of phloridzin in Chinese hamster ovary (CHO) cells, both untransfected and transfected with SGLT1 (Lin et al., 1998). Because these cells have been shown to express the MRP1 transporter (Barnouin et al., 1998), we used the MRP1/MRP2 inhibitor MK-571 (Jedlitschky et al., 1994, 1996; Walle et al., 1999b; Walgren et al., 2000a) to modify this transporter. We also used Madin-Darby canine kidney (MDCK) cells, both untransfected and transfected with MRP2 (MRP2-MDCK) (Evers et al., 1998), as well as human colonic Caco-2 cells, to determine the potential involvement of MRP2 in the transport of phloridzin.

	Materials and Methods

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Materials. Phloridzin and phloretin (structures in Fig. 1), genistin, diosmin, rutin, and buthionine-[S,R]-sulfoximine (BSO) were obtained from Sigma-Aldrich (St. Louis, MO). Quercetin-4'-O-glucoside was prepared as previously described (Walgren et al., 1998). MK-571 was a generous gift from Dr. A. W. Ford-Hutchinson, Merck-Frosst Centre for Therapeutic Research (Pointe Claire-Dorval, QC, Canada). Parental CHO cells and SGLT1-transfected G6D3 cells (Lin et al., 1998) were a generous gift from Drs. J.-T. Lin and R. K.-H. Kinne, Max Planck Institut für Molekulare Physiologie (Dortmund, Germany). Parental Madin-Darby canine kidney (MDCKII) cells and MRP2-transfected MDCKII cells (MRP2-MDCK) (Evers et al., 1998) were kindly provided by Professor P. Borst, Netherlands Cancer Institute (Amsterdam, the Netherlands). Fetal calf serum was obtained from Summit Biotechnology (Ft. Collins, CO), and other cell culture supplies were obtained from Mediatech (Herndon, VA).

Cell Culture. MDCK and MRP2-MDCK cells were cultured in Dulbecco's modified Eagle's medium with 10% fetal calf serum, penicillin, and streptomycin. CHO and G6D3 cells were cultured in the same medium with the addition of nonessential amino acids, 1 mM sodium pyruvate, and 25 µM ß-mercaptoethanol. The G6D3 medium also contained 0.4 mg/ml G418 to maintain selection. The cells were maintained in a humidified incubator with 10% carbon dioxide. Caco-2 cells (American Type Culture Collection, Manassas, VA) were cultured in Earle's minimum essential medium with nonessential amino acids and 10% fetal calf serum in a 5% carbon dioxide incubator.

Cellular Uptake of Phloridzin and Flavonoid Glycosides. All cells were grown in six-well plates until just confluent (3 days for CHO and MDCK parent and transfected cells, and 7 days for Caco-2 cells). The cell monolayers were washed twice for 30 min with Hanks' buffer (pH 7.4) in a 37°C incubator and then incubated with 50 µM phloridzin in Hanks' buffer for 4 min (CHO cells) or 30 min (MDCK and Caco-2 cells). When MK-571 (50 µM) was used, it was added to the second buffer wash and together with the glycosides. The cell monolayers were rinsed rapidly three times with ice-cold saline and extracted twice with 1 ml of methanol on an orbital shaker for 10 min. The combined methanol extracts were evaporated to dryness and reconstituted in mobile phase. The cell extracts were analyzed by HPLC as described below. CHO parent and SGLT1-transfected cells were also incubated with the flavonoid glycosides diosmin, genistin, quercetin-4'-O-glucoside, and rutin in an identical fashion. In some experiments, we attempted to deplete the cellular glutathione levels by preincubation of MDCK-MRP2 cells with BSO for 24 h (Oda et al., 1999). Intracellular glutathione levels were measured with a kit from Calbiochem (San Diego, CA).

HPLC Analysis. Phloridzin samples were analyzed on a Waters (Milford, MA) HPLC system consisting of a model 717 Plus autosampler, a model 510 pump, and a model 996 photodiode array detector with a Millennium software system. A Symmetry C18, 3.9 x 150 mm column (Waters) was used with a mobile phase of methanol/glacial acetic acid/water (35:5:60) at a flow rate of 0.9 ml/min and detection at 283 nm. Diosmin, genistin, quercetin-4'-O-glucoside, and rutin were analyzed similarly with detection at 343, 260, 370, and 370 nm, respectively.

Immunoblot Analyses. The presence of MRP1 protein in CHO and G6D3 cells was confirmed by Western blotting, using two commercial antibodies, QCRL-1 (Hipfner et al., 1994) and MRP1m6 (Kamiya Biomedical, Thousand Oaks, CA), with cell membranes prepared and immunoblotting done as described (Almquist et al., 1995). PANC-1 cell membranes were used as a positive control (Miller et al., 1996).

Statistical Analysis. Differences between treatment groups were assessed by unpaired Student's t test. p values of <0.05 were considered significant. All values are given as means ± S.E.M.

	Results

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To examine the transport of phloridzin, we used a cellular uptake approach. The cells used, i.e., CHO, MDCK, and Caco-2 cells, were grown in six-well plates until confluent, after which they were incubated with phloridzin or other flavonoid glycosides, in buffer. After washing the cells repeatedly with cold buffer, any phloridzin that had been taken up by the cells was extracted from the cells with methanol and determined quantitatively by HPLC. This procedure has previously been shown to effectively lyse cells as well as extract flavonoid glycosides (Walgren et al., 2000b). There were no interferences in this assay from other biological components and neither was any metabolism of phloridzin, e.g., to phloretin, detected during the relatively short time courses studied (4 or 30 min). The concentration of phloridzin studied, i.e., 50 µM, provides effective inhibition of SGLT1 (Toggenburger et al., 1982) and is a concentration that might be found in the intestinal lumen after dietary consumption (Walgren et al., 1998). The linearity of uptake of phloridzin with time by either the CHO, MDCK, or Caco-2 cells could not be determined accurately because of the limited sensitivity of the HPLC/UV method. The 4-min incubation time used for the CHO cells and the 30 min for MDCK and Caco-2 cells were the shortest times giving accurate uptake measurements.

Studies in CHO Cells. The 4-min uptake of phloridzin in the nontransfected CHO cells was 90 ± 8 pmol/mg protein (mean ± S.E.M.). In the SGLT1-transfected CHO cells (G6D3), the accumulation of phloridzin was significantly higher, 154 ± 18 pmol/mg protein (p < 0.01; n = 17; Fig. 2A), suggesting SGLT1 to be involved in this uptake. A previous study (Barnouin et al., 1998) had identified a high expression of the MRP1 transporter in CHO cells. Using immunoblotting with two MRP1 antibodies, we confirmed its presence in both G6D3 and parent cells. Since a recent study in our laboratory had demonstrated that another flavonoid glucoside was an MRP2 substrate (Walgren et al., 2000a), we determined the effect of the MRP1/MRP2 inhibitor MK-571 (Jedlitschky et al., 1994, 1996; Walle et al., 1999b; Walgren et al., 2000a) on the cellular accumulation of phloridzin. In the presence of 50 µM MK-571, the accumulation of phloridzin in the CHO cells increased 3.7-fold to 332 ± 51 pmol/mg protein (p < 0.001; Student's unpaired t test), whereas in the G6D3 cells the MK-571 caused an 8-fold increase to 1,229 ± 136 pmol/mg protein (p < 0.0001; n = 17; Fig. 2A).

View larger version (39K): [in this window] [in a new window]   FIG. 2. Cellular uptake of phloridzin (50 µM) in the absence and presence of 50 µM MK-571 by untransfected CHO cells () and SGLT1-transfected CHO cells (G6D3) () (A); and untransfected MDCK cells () and MRP2-transfected MDCK cells (MRP2/MDCK) () (B). *, higher than without MK-571, p < 0.01; **, higher than in untransfected CHO cells, p < 0.001; ***, lower than in untransfected MDCK cells, p < 0.01; n = 17 for all groups in A and n = 6 in all groups in B.

To further support the involvement of SGLT1 in phloridzin uptake, additional experiments were done with G6D3 cells in the presence of 50 µM MK-571. First, in the presence of 30 mM glucose, the uptake of 50 µM phloridzin was inhibited by 40% from 913 ± 56 to 548 ± 158 pmol/mg protein (p < 0.05; n = 6). This inhibition was of a magnitude similar to that previously reported for the uptake of quercetin-4'-O-glucoside in these cells (Walgren et al., 2000b). Second, the concentration dependence of the phloridzin uptake was investigated. As shown in Fig. 3, the uptake followed Michaelis-Menten kinetics with an apparent K_m value of 1,020 µM and a V_max value of 7.3 nmol/mg protein/min.

View larger version (17K): [in this window] [in a new window]   FIG. 3. Cellular uptake of phloridzin in G6D3 cells in the presence of 50 µM MK-571. Means ± S.E.M. are shown. n = 3.

Similar uptake experiments were done with the nontransfected CHO cells. In the presence of MK-571 the uptake was linear with increasing phloridzin concentrations up to at least 250 µM, suggesting either passive uptake or uptake by an unknown transporter with a high K_m value. In the absence of MK-571, the uptake was much reduced (cf. Fig. 2A) and appeared to follow Michaelis-Menten kinetics up to 250 µM.

The studies with phloridzin were then extended to include several other glycosides of common flavonoids (Table 1). Although these glycosides, like phloridzin, showed a higher accumulation in the G6D3 cells compared with the CHO cells, this was not statistically significant. In the CHO cells, 50 µM MK-571 produced significantly higher accumulation of quercetin-4'-O-glucoside, rutin, and, in particular, diosmin, the latter almost a 10-fold increase. Although genistin accumulation also was higher in the presence of MK-571, this was not significant. Similarly, 50 µM MK-571 caused cellular increases of all four glycosides in the G6D3 cells, again with diosmin having an almost 10-fold increase. When comparing the uptake in the G6D3 cells to the CHO cells in the presence of MK-571, both genistin and quercetin-4'-O-glucoside showed significantly higher accumulation in the G6D3 cells, 2.4-fold and 2.0-fold, respectively, similar to phloridzin (cf. Fig. 2A). These data were the result of at least six independent measurements (Table 1).

Studies in MDCK and Caco-2 Cells. The 30-min accumulation of phloridzin in the untransfected MDCK cells, studied in a manner similar to that of the CHO cells, was 82 ± 15 pmol/mg protein. MK-571 had no effect on this accumulation, although these cells do express some MRP2 (Evers et al., 1998). The expression of MRP2 protein in the MDCKMRP2 cells and to a smaller extent in the parent cells has recently been confirmed in our laboratory (Vaidyanathan and Walle, 2003). The accumulation of phloridzin in the MRP2-transfected MDCK cells was 50% lower, 49 ± 3 pmol/mg protein (p < 0.05), supporting the notion that phloridzin is a substrate for MRP2 efflux. When 50 µM MK-571 was added to these cells, the accumulation increased 3.6-fold to 178 ± 8 pmol/mg protein (p < 0.01; n = 6; Fig. 2B).

Preincubation of MDCK-MRP2 cells for 24 h with 5 mM BSO (Oda et al., 1999), a treatment that reduced the cellular glutathione levels to 29% of control (p < 0.05), did not significantly increase the uptake of phloridzin.

Previous studies have shown that Caco-2 cells express both MRP2 and SGLT1 (Walgren et al., 2000a,b). The 30-min accumulation of phloridzin in these cells was 33.7 ± 1.7 pmol/mg protein. In the presence of 50 µM MK-571, this accumulation increased to 41.4 ± 1.4 pmol/mg protein (p < 0.01; n = 6), consistent with a low apical expression of MRP2 in these cells.

	Discussion

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This study suggests that phloridzin, a specific inhibitor of SGLT1 transport, is itself transported by SGLT1. This is in contrast to previous determinations (Toggenburger et al., 1982). This new observation was made possible by the use of SGLT1-transfected cells (Lin et al., 1998). The uptake of phloridzin by the transfected CHO cells was, however, only about 70% higher than in the untransfected cells.

Two recent observations have suggested that flavonoid glucosides unexpectedly may use MRPs for their transmembrane efflux transport (Walle et al., 1999a; Walgren et al., 2000a). The use of MK-571, a well established MRP1/MRP2 transport inhibitor (Jedlitschky et al., 1994, 1996; Walle et al., 1999b; Walgren et al., 2000a), in our phloridzin uptake experiments revealed a 3.7-fold increased uptake in the untransfected CHO cells, but as much as an 8-fold increase in the SGLT1-transfected cells (Fig. 2A). A high level of MRP1 expression has indeed been reported in the CHO cells (Barnouin et al., 1998) and was confirmed in our study. When comparing the G6D3 cells with the CHO cells, in the presence of MK-571 there was a 3.7-fold higher accumulation of phloridzin in the SGLT1-transfected cells. Thus, MRP1 expression in the G6D3 cells appeared to have partially masked SGLT1-mediated cellular uptake. The observations in the untransfected CHO cells with and without MK-571 indicate that phloridzin can be taken up without SGLT1. However, in the presence of SGLT1 and inhibition of MRP1, the uptake was greatly facilitated.

The uptake of phloridzin by SGLT1 in the presence of MK-571 inhibition was further supported by its inhibition by 30 mM glucose. Also, in the presence of MK-571, the uptake of phloridzin by the G6D3 cells showed clear saturation kinetics (Fig. 3) with apparent K_m and V_max values similar to those for -methylglucose (Lin et al., 1998).

Our studies with the CHO cells were also expanded to glycosides of several other flavonoids. Findings were similar to those for phloridzin, both with regard to SGLT1 uptake and MRP1-mediated efflux, although the data were somewhat less clear. However, both genistin and quercetin-4'-O-glucoside demonstrated increased uptake in the G6D3 cells compared with the parent CHO cells in the presence of MK-571. Also, diosmin, a clinically used flavonoid (Garner et al., 2002), was found to be an unusually good substrate for the efflux by MRP1. It should, however, be emphasized that in view of the many MRP isoforms being identified (Dean et al., 2001), it is conceivable that the CHO cells may contain other MRP isoforms in addition to MRP1.

The ability of MRP transporters, e.g., MRP1 and MRP2, to use phloridzin as a substrate was also tested with the MRP2-transfected MDCK cells. Consistent with MRP2 being involved in phloridzin transport was the finding of a lower accumulation in the MRP2-transfected cells as compared with the parent cells, as well as the dramatically increased uptake in the transfected cells in the presence of MK-571 (Fig. 2B). In addition, we also examined phloridzin uptake by Caco-2 cells, well known to express MRP2 (Walle et al., 1999b; Walgren et al., 2000a). In these experiments we also observed increased cell uptake in the presence of MK-571.

The finding that phloridzin and other flavonoid glycosides appear to be substrates for and thus transported by MRP transporters, together with a previous observation on quercetin-4'-O-glucoside in our laboratory (Walgren et al., 2000a), is a novel observation. These flavonoid glycosides are neutral molecules at physiological pH and therefore constitute a new group of substrates for these transporters. It may not involve cotransport with glutathione as it does for vinblastine (Evers et al., 2000), since reduction of cellular content of glutathione by 71% using BSO had no effect on phloridzin transport, although this should be further examined. Thus, the exact mechanism of this transport is not known.

In summary, this study indicates a complex interplay between one of the most important apical absorptive transporters, i.e., SGLT1, and MRP efflux transport. The finding that the phloridzin uptake in SGLT1-transfected versus untransfected CHO cells was so much greater in the absence versus presence of functional MRP1 may even suggest a functional linkage between these two opposing transporters. Attempts to improve drug absorption are being made by using SGLT1 to shuttle glucosylated drugs across the apical membrane in the intestine (Tsuji and Tamai, 1996). However, in view of our findings in this study, such efforts may be counteracted by MRP-mediated efflux.

Thomas Walle
U. Kristina Walle

Department of Cell and Molecular Pharmacology and Experimental Therapeutics Medical University of South Carolina Charleston, South Carolina

	Acknowledgments

 
We thank Dr. R. A. Walgren for valuable discussions leading toward this project. We are deeply grateful to Drs. J.-T. Lin and R. K.-H. Kinne for the G6D3 cells and Dr. P. Borst for the MDCK-MRP2 cells.

	Footnotes

 
This study was supported by National Institutes of Health Grant GM55561. It was presented in part at the 2002 American Association of Pharmaceutical Scientists Annual Meeting, Toronto, Ontario, Canada, November 10-14, 2002.

¹ Abbreviations used are: SGLT1, sodium-dependent glucose transporter 1; MRP, multidrug resistance-associated protein; CHO, Chinese hamster ovary; G6D3, SGLT1-transfected CHO cells; MK-571, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid; MDCK, Madin-Darby canine kidney; BSO, buthionine-[S,R]-sulfoximine; HPLC, high performance liquid chromatography.

Address correspondence to: Dr. Thomas Walle, Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, P.O. Box 250505, Charleston, SC 29425. E-mail: wallet{at}musc.edu

	References

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