Sodium-dependent glucose transporter 1 and glucose transporter 2 mediate intestinal transport of quercetrin in Caco-2 cells

  • Suyun Li Beijing Shijitan Hospital, Capital Medical University, Beijing, and Department of Nutrition, Tianjin Institute of Environmental and Operational Medicine, Tianjing, China
  • Jin Liu Systems Engineering Research Institute, Beijing, China
  • Zheng Li Beijing Institute of Pharmacology & Toxicology, Beijing, China
  • Liqin Wang Department of Epidemiology and Statistics, Hebei Medical University, Shijiazhuang, China
  • Weina Gao Department of Nutrition, Tianjin Institute of Environmental and Operational Medicine, Tianjing, China
  • Zhenqing Zhang Beijing Institute of Pharmacology & Toxicology, Beijing, China
  • Changjiang Guo Department of Nutrition, Tianjin Institute of Environmental and Operational Medicine, Tianjing, China
Keywords: flavonoid, phloridzin; phloretin; Caco-2 cell monolayer; transmembrane transport; absorption

Abstract

The role of glucose transporters in the transport of flavonoids remains ambiguous. In this study, we examined whether quercetrin would be uptaken and transported intactly in modeled Caco-2 cells, as well as to determine the involvements of sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) in its transmembrane transport. The uptake experiment was conducted in Caco-2 cells 24 hours after seeded and the transport experiment was conducted in Caco-2 cells after 21 days of culturing in a Millicell system. Quercetrin was administered at 3, 9 or 18 µg/mL; and the timepoints of sampling were 30, 60, 90, 120, and 150 min. In the uptake experiment, the highest intracellular quercetrin concentration was observed in the cells treated with 18 µg/mL quercetrin at 60 min, with a bell-shaped kinetic curve. Quercetin, isorhamnetin, and tamarixetin were detected inside the cells, particularly when treated with the high dose. In the transport experiment, quercetrin was transported from the apical to basolateral side and vice versa; its concentrations depended on dose, time, and transport direction. Only trace amounts of isorhamnetin and tamarixetin were detected in the apical chamber when quercetrin was added to the basolateral chamber. Phloridzin and phloretin, a potent inhibitor of SGLT1 and GLUT2, respectively, significantly diminished quercetrin transport from the apical to basolateral side; and phloretin had a larger inhibitory effect than phloridzin. In conclusion, our results demonstrate that quercetrin is absorbed intactly and then effluxed out of Caco-2 cells through both apical and basolateral membranes probably via SGLT1 and GLUT2.

Downloads

Download data is not yet available.

References


  1. Koch W. Dietary polyphenols-important non-nutrients in the prevention of chronic noncommunicable diseases. A systematic review. Nutrients 2019; 11: 1039. doi: 10.3390/nu11051039

  2. Costa C, Tsatsakis A, Mamoulakis C, Teodoro M, Briguglio G, Caruso E, et al. Current evidence on the effect of dietary polyphenols intake on chronic diseases. Food Chem Toxicol 2017; 110: 286–99. doi: 10.1016/j.fct.2017.10.023

  3. Fraga CG, Croft KD, Kennedy DO, Tomas-Barberan FA. The effects of polyphenols and other bioactives on human health. Food Funct 2019; 10: 514–28. doi: 10.1039/C8FO01997E

  4. Poti F, Santi D, Spaggiari G, Zimetti F, Zanotti I. Polyphenol health effects on cardiovascular and neurodegenerative disorders: a review and meta-analysis. Int J Mol Sci 2019; 20: pii: E351. doi: 10.1530/endoabs.63.P637

  5. Xiao J. Dietary flavonoid aglycones and their glycosides: which show better biological significance? Crit Rev Food Sci Nutr 2017; 57: 1874–905.

  6. Shahidi F, Yeo J. Bioactivities of phenolics by focusing on suppression of chronic diseases: a review. Int J Mol Sci 2018; 19: 1753. doi: 10.3390/ijms19061573

  7. Gonzales GB, Smagghe G, Grootaert C, Zotti M, Raes K, Van Camp J. Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure-activity/property relationship-based approach in the study of bioavailability and bioactivity. Drug Metab Rev 2015; 47: 175–90. doi: 10.3109/03602532.2014.1003649

  8. Beecher GR. Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr 2003; 133: 3248s–54s. doi: 10.1093/jn/133.10.3248S

  9. Kawai Y. Understanding metabolic conversions and molecular actions of flavonoids in vivo: toward new strategies for effective utilization of natural polyphenols in human health. J Med Invest 2018; 65: 162–5. doi: 10.2152/jmi.65.162

  10. Mauri PL, Iemoli L, Gardana C, Riso P, Simonetti P, Porrini M, et al. Liquid chromatography/electrospray ionization mass spectrometric characterization of flavonol glycosides in tomato extracts and human plasma. Rapid Commun Mass Spectrom 1999; 13: 924–31. doi: 10.1002/(SICI)1097-0231(19990530)13:10%3C924::AID-RCM588%3E3.0.CO;2-G

  11. Paganga G, Rice-Evans CA. The identification of flavonoids as glycosides in human plasma. FEBS Lett 1997, 401: 78–82. doi: 10.1016/S0014-5793(96)01442-1

  12. Aziz AA, Edwards CA, Lean ME, Crozier A. Absorption and excretion of conjugated flavonols, including quercetin-4'-O-beta-glucoside and isorhamnetin-4'-O-beta-glucoside by human volunteers after the consumption of onions. Free Radic Res 1998; 29: 257–69. doi: 10.1080/10715769800300291

  13. Day AJ, Williamson G. Biomarkers for exposure to dietary flavonoids: a review of the current evidence for identification of quercetin glycosides in plasma. Br J Nutr 2001; 86 Suppl 1: S105–10. doi: 10.1079/BJN2001342

  14. Morand C, Manach C, Crespy V, Remesy C. Quercetin 3-O-beta-glucoside is better absorbed than other quercetin forms and is not present in rat plasma. Free Radic Res 2000; 33: 667–76. doi: 10.1080/10715760000301181

  15. Fang Y, Cao W, Xia M, Pan S, Xu X. Study of structure and permeability relationship of flavonoids in Caco-2 Cells. Nutrients 2017; 9: 1301. doi: 10.3390/nu9121301

  16. Walgren RA, Lin JT, Kinne RK, Walle T. Cellular uptake of dietary flavonoid quercetin 4'-beta-glucoside by sodium-dependent glucose transporter SGLT1. J Pharmacol Exp Ther 2000; 294: 837–43.

  17. Wolffram S, Block M, Ader P. Quercetin-3-glucoside is transported by the glucose carrier SGLT1 across the brush border membrane of rat small intestine. J Nutr 2002; 132: 630–5. doi: 10.1093/jn/132.4.630

  18. Roder PV, Geillinger KE, Zietek TS, Thorens B, Koepsell H, Daniel H. The role of SGLT1 and GLUT2 in intestinal glucose transport and sensing. PLoS One 2014; 9: e89977. doi: 10.1371/journal.pone.0089977

  19. Cermak R, Landgraf S, Wolffram S. Quercetin glucosides inhibit glucose uptake into brush-border-membrane vesicles of porcine jejunum. Br J Nutr 2004; 91: 849–55. doi: 10.1079/BJN20041128

  20. Kwon O, Eck P, Chen S, Corpe CP, Lee JH, Kruhlak M, et al. Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. Faseb J 2007; 21: 366–77. doi: 10.1096/fj.06-6620com

  21. Farrell TL, Ellam SL, Forrelli T, Williamson G. Attenuation of glucose transport across Caco-2 cell monolayers by a polyphenol-rich herbal extract: interactions with SGLT1 and GLUT2 transporters. Biofactors 2013; 39: 448–56. doi: 10.1002/biof.1090

  22. Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci 2016; 5: e47. doi: 10.1017/jns.2016.41

  23. Romero M, Vera B, Galisteo M, Toral M, Galvez J, Perez-Vizcaino F, et al. Protective vascular effects of quercitrin in acute TNBS-colitis in rats: the role of nitric oxide. Food Funct 2017; 8: 2702–11. doi: 10.1039/C7FO00755H

  24. Galvez J, Sanchez de Medina F, Jimenez J, Torres MI, Fernandez MI, Nunez MC, et al. Effect of quercitrin on lactose-induced chronic diarrhoea in rats. Planta Med 1995; 61: 302–6. doi: 10.1055/s-2006-958088

  25. Galvez J, Zarzuelo A, Crespo ME, Lorente MD, Ocete MA, Jimenez J. Antidiarrhoeic activity of Euphorbia hirta extract and isolation of an active flavonoid constituent. Planta Med 1993; 59: 333–6. doi: 10.1055/s-2006-959694

  26. Kumar S, Malhotra R, Kumar D. Euphorbia hirta: its chemistry, traditional and medicinal uses, and pharmacological activities. Pharmacogn Rev 2010; 4: 58–61. doi: 10.4103/0973-7847.65327

  27. Zhang Y, Guo Y, Wang M, Dong H, Zhang J, Zhang L. Quercetrin from Toona sinensis leaves induces cell cycle arrest and apoptosis via enhancement of oxidative stress in human colorectal cancer SW620 cells. Oncol Rep 2017; 38: 3319–26. doi: 10.3892/or.2017.6042

  28. Chiow KH, Phoon MC, Putti T, Tan BK, Chow VT. Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection. Asian Pac J Trop Med 2016; 9: 1–7. doi: 10.1016/j.apjtm.2015.12.002

  29. Yang C, Li Z, Zhang T, Liu F, Ruan J, Zhang Z. Transcellular transport of aconitine across human intestinal Caco-2 cells. Food Chem Toxicol 2013; 57: 195–200. doi: 10.1016/j.fct.2013.03.033

  30. Zou TB, Feng D, Song G, Li HW, Tang HW, Ling WH. The role of sodium-dependent glucose transporter 1 and glucose transporter 2 in the absorption of cyanidin-3-o-beta-glucoside in Caco-2 cells. Nutrients 2014; 6: 4165–77. doi: 10.3390/nu6104165

  31. Justino GC, Santos MR, Canario S, Borges C, Florencio MH, Mira L. Plasma quercetin metabolites: structure-antioxidant activity relationships. Arch Biochem Biophys 2004; 432: 109–21. doi: 10.1016/j.abb.2004.09.007

  32. Santos MR, Rodriguez-Gomez MJ, Justino GC, Charro N, Florencio MH, Mira L. Influence of the metabolic profile on the in vivo antioxidant activity of quercetin under a low dosage oral regimen in rats. Br J Pharmacol 2008; 153: 1750–61. doi: 10.1038/bjp.2008.46

  33. Bohn T, McDougall GJ, Alegria A, Alminger M, Arrigoni E, Aura AM, et al. Mind the gap-deficits in our knowledge of aspects impacting the bioavailability of phytochemicals and their metabolites--a position paper focusing on carotenoids and polyphenols. Mol Nutr Food Res 2015; 59: 1307–23. doi: 10.1002/mnfr.201400745

  34. Hollman PC, de Vries JH, van Leeuwen SD, Mengelers MJ, Katan MB. Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. Am J Clin Nutr 1995; 62: 1276–82. doi: 10.1093/ajcn/62.6.1276

  35. Gee JM, DuPont MS, Rhodes MJ, Johnson IT. Quercetin glucosides interact with the intestinal glucose transport pathway. Free Radic Biol Med 1998; 25: 19–25. doi: 10.1016/S0891-5849(98)00020-3

  36. Gorboulev V, Schurmann A, Vallon V, Kipp H, Jaschke A, Klessen D, et al. Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 2012; 61: 187–96. doi: 10.2337/db11-1029

  37. Song P, Onishi A, Koepsell H, Vallon V. Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus. Expert Opin Ther Targets 2016; 20: 1109–25. doi: 10.1517/14728222.2016.1168808

  38. Crespy V, Morand C, Besson C, Manach C, Demigne C, Remesy C. Comparison of the intestinal absorption of quercetin, phloretin and their glucosides in rats. J Nutr 2001; 131: 2109–14. doi: 10.1093/jn/131.8.2109

  39. Raja M, Kinne RK. Identification of phlorizin binding domains in sodium-glucose cotransporter family: SGLT1 as a unique model system. Biochimie 2015; 115: 187–93. doi: 10.1016/j.biochi.2015.06.003

  40. Kellett GL, Brot-Laroche E, Mace OJ, Leturque A. Sugar absorption in the intestine: the role of GLUT2. Annu Rev Nutr 2008; 28: 35–54. doi: 10.1146/annurev.nutr.28.061807.155518

  41. Day AJ, DuPont MS, Ridley S, Rhodes M, Rhodes MJ, Morgan MR, et al. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver beta-glucosidase activity. FEBS Lett 1998; 436: 71–5. doi: 10.1016/S0014-5793(98)01101-6

  42. Day AJ, Canada FJ, Diaz JC, Kroon PA, McLauchlan R, Faulds CB, et al. Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Lett 2000; 468: 166–70. doi: 10.1016/S0014-5793(00)01211-4

  43. Walle T. Methylation of dietary flavones greatly improves their hepatic metabolic stability and intestinal absorption. Mol Pharm 2007; 4: 826–32. doi: 10.1021/mp700071d

  44. Cao H, Jing X, Wu D, Shi Y. Methylation of genistein and kaempferol improves their affinities for proteins. Int J Food Sci Nutr 2013; 64: 437–43. doi: 10.3109/09637486.2012.759186

  45. Aragonès G, Danesi F, Del Rio D, Mena P. The importance of studying cell metabolism when testing the bioactivity of phenolic compounds. Trends Food Sci Tech 2017; 69: 230–42. doi: 10.1016/j.tifs.2017.02.001

Published
2020-06-15
How to Cite
Li S., Liu J., Li Z., Wang L., Gao W., Zhang Z., & Guo C. (2020). Sodium-dependent glucose transporter 1 and glucose transporter 2 mediate intestinal transport of quercetrin in Caco-2 cells. Food & Nutrition Research, 64. https://doi.org/10.29219/fnr.v64.3745
Section
Original Articles