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Institute of Animal Nutrition, Physiology and Metabolism, University of Kiel, D-24098 Kiel, Germany
Dear Editor:
First we would like to thank Dr. Arts, Dr. Sesink and Dr. Hollman for critically reading and commenting on our recent paper concerning the involvement of the Na+-dependent glucose carrier SGLT1 in the absorption of quercetin from quercetin glucosides by rat small intestine (1
). Our conclusion that SGLT1 is involved in mucosal uptake of intact quercetin glucosides was based mainly on the following findings. The disappearance of quercetin-3-O-glucoside (Q-3-Gluc) was significantly reduced either in the presence of D-glucose or by omitting Na+ from the mucosal bathing solution and adding phloridzin; these effects were observed only when substances were added to the mucosal side of rat jejunum. They were restricted to the small intestine and were not observed in the proximal colon. We fully agree with Arts et al. that all but one of the experimental manipulations thought to inhibit SGLT-1 could also inhibit intestinal lactase-phloridzin hydrolase (LPH). The one finding that can not be explained by an inhibition of LPH is the Na+ dependence of the effect. We are not aware of any report of a Na+ dependence of LPH or an inhibition of this enzyme by choline (which was used to replace Na+). This indeed was the major reason for favoring a role of SGLT-1 rather than of LPH in the absorption of quercetin from Q-3-Gluc. We have critically discussed this point in our publication (1
).
Although it is correct that Q-3-Gluc is a poor substrate for the broad-specificity ß-glucosidase in human and rat enterocytes (2
,3
), the lack of appearance of quercetin conjugates despite the appearance of free quercetin in the mucosal medium (and also in the intestinal mucosa) is not proof for an exclusive extracellular hydrolysis of Q-3-Gluc by LPH as suggested by Arts et al. Rapid conjugation of quercetin should occur not only after intracellular hydrolysis but also after diffusive uptake of free quercetin after extracellular hydrolysis by LPH. It has been repeatedly demonstrated in perfusion studies as well as in in vivo studies on the bioavailability of quercetin that irrespective of the quercetin source (free quercetin, quercetin glucosides, quercetin glucorhamnoside), only conjugated quercetin and to a minor extent, conjugated methylated derivatives of quercetin, appear within the circulation and that conjugation has already occurred in the mucosa of the small intestine (4
–6
). Finally, Walgren et al. (7
) have reported strong evidence for the transport of intact quercetin-4'-glucoside by SGLT-1 into Chinese hamster ovary cells stably transfected with rabbit SGLT-1 but not in cells that do not express this carrier mechanism.
Taken together, our results are not a final proof for transport of intact Q-3-Gluc by SGLT1 but are best explained by an involvement of this transport mechanism. This does not rule out that extracellular hydrolysis of quercetin glucosides by LPH occurs in parallel.
Manuscript received 18 June 2002. Revision accepted 21 June 2002.
LITERATURE CITED
1. Wolffram, S., Blöck, M. & Ader, P. (2002) Quercetin-3-glucoside is transported by the glucose carrier SGLT1 across the brush border membrane of rat small intestine. J. Nutr. 132:630-635.
2. Day, A. J., DuPont, M. S., Ridley, S., Thodes, M., Thodes, M.J.C., Morgan, M.R.A. & Williamson, G. (1998) Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver ß-glucosidase activity. FEBS Lett. 436:71-75.[Medline]
3. Ioku, K., Pongpiriyadacha, Y., Konishi, Y., Takei, Y., Nakatani, N. & Terao, N. (1998) ß-Glucosidase activity in the rat small intestine toward quercetin monoglucosides. Biosci. Biotechnol. Biochem. 62:1428-1431.[Medline]
4. Crespy, V., Morand, C., Manach, C., Besson, C., Demigné, C. & Rémésy, C. (1999) Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. Am. J. Physiol. 277:G120-G126.
5. Ader, P., Weßmann, A. & Wolffram, S. (2000) Bioavailability and metabolism of the flavonol quercetin in the pig. Free Radic. Biol. Med. 28:1056-1067.[Medline]
6. Graefe, E. U., Wittig, J., Mueller, S., Tiethling, A. K., Uehleke, B., Drewelow, B., Pforte, H., Jacobasch, G., Derendorf, H. & Veit, M. (2001) Pharmacokinetics and bioavailability of quercetin glycosides in humans. J. Clin. Pharmacol. 41:492-499.[Abstract]
7. Walgren, R. A., Lin, J.-T., Kinne, R. K.-H. & Walle, T. (2000) Cellular uptake of dietary flavonoid quercetin-4'-ß-glucoside by sodium-dependent glucose transporter SGLT1. J. Pharmacol. Exp. Ther. 294:837-843.
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