Journal of Natural Medicines

, Volume 71, Issue 1, pp 131–138 | Cite as

Ginsenosides, ingredients of the root of Panax ginseng, are not substrates but inhibitors of sodium-glucose transporter 1

  • Shengli Gao
  • Hirotaka Kushida
  • Toshiaki Makino
Original Paper


Recent pharmacokinetic studies have revealed that ginsenosides, the major ingredients of ginseng (the roots of Panax ginseng), are present in the plasma collected from subjects receiving ginseng, and speculated that ginsenosides might be actively transported via glucose transporters. We evaluated whether ginsenosides Rb1 and Rg1, and their metabolites from enteric bacteria act as substrates of sodium-glucose cotransporter (SGLT) 1, the major glucose transporter expressed on the apical side of intestinal epithelial cells. First, we evaluated the competing effects of ginseng extract and ginsenosides on the uptake of [14C]methyl-glucose, a substrate of SGLT1, by SGLT1-overexpressing HEK293 cells. A boiling water extract of ginseng inhibited SGLT1 in a concentration-dependent manner with an IC50 value of 0.85 mg/ml. By activity-guided fractionation, we determined that the fraction containing ginsenosides displayed an inhibitory effect on SGLT1. Of the ginsenosides evaluated, protopanaxatriol-type ginsenosides were not found to inhibit SGLT1, whereas protopanaxadiol-type ginsenosides, including ginsenosides Rd, Rg3, Rh2, F2 and compound K, exhibited significant inhibitory effects on SGLT1, with ginsenoside F2 having the highest activity with an IC50 value of 23.0 µM. Next, we measured the uptake of ginsenoside F2 and compound K into Caco-2 cells, a cell line frequently used to evaluate the intestinal absorption of drugs. The uptake of ginsenoside F2 and compound K into Caco-2 cells was not competitively inhibited by glucose. Furthermore, the uptake of ginsenoside F2 and compound K into SGLT1-overexpressing HEK293 cells was not significantly higher than into mock cells. Ginsenoside F2 and compound K did not appear to be substrates of SGLT1, although these compounds could inhibit SGLT1. Ginsenosides might be absorbed by passive diffusion through the intestinal membrane or actively transported via unknown transporters other than SGLT1.


Panax ginseng Ginsenosides Glucose transporter SGLT1 Diabetes 



We are grateful to Prof. Katsuhisa Inoue, Laboratory of Molecular Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, for technical support to construct human SGLT1-plasmid.


  1. 1.
    Pharmaceutical and Medical Device Regulatory Science Society of Japan (2016) The Japanese Pharmacopoeia seventeenth Edition (JPXVI). Jiho, TokyoGoogle Scholar
  2. 2.
    Bensky D, Clavey S, Stöger E (2004) Chinese herbal medicine—Materia Medica, 3rd edn. Eastland Press, SeattleGoogle Scholar
  3. 3.
    Akao T, Kanaoka M, Kobashi K (1998) Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration—measurement of compound K by enzyme immunoassay. Biol Pharm Bull 21:245–249CrossRefPubMedGoogle Scholar
  4. 4.
    Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M (2003) Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos 31:1065–1071CrossRefPubMedGoogle Scholar
  5. 5.
    Munekage M, Kitagawa H, Ichikawa K, Watanabe J, Aoki K, Kono T, Hanazaki K (2011) Pharmacokinetics of daikenchuto, a traditional Japanese medicine (kampo) after single oral administration to healthy Japanese volunteers. Drug Metab Dispos 39:1784–1788CrossRefPubMedGoogle Scholar
  6. 6.
    Liu H, Yang J, Du F, Gao X, Ma X, Huang Y, Xu F, Niu W, Wang F, Mao Y, Sun Y, Lu T, Liu C, Zhang B, Li C (2009) Absorption and disposition of ginsenosides after oral administration of Panax notoginseng extract to rats. Drug Metab Dispos 37:2290–2298CrossRefPubMedGoogle Scholar
  7. 7.
    Zou TB, Feng D, Song G, Li HW, Tang HW, Ling WH (2014) The role of sodium-dependent glucose transporter 1 and glucose transporter 2 in the absorption of cyanidin-3-O-β-glucoside in caco-2 cells. Nutrients 6:4165–4177CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Xiong J, Sun M, Guo J, Huang L, Wang S, Meng B, Ping Q (2009) Active absorption of ginsenoside Rg1 in vitro and in vivo: the role of sodium-dependent glucose co-transporter 1. J Pharm Pharmacol 61:381–386PubMedGoogle Scholar
  9. 9.
    Choi J, Kim TH, Choi TY, Lee MS (2013) Ginseng for health care: a systematic review of randomized controlled trials in Korean literature. PLoS One 8:e59978CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Shishtar E, Sievenpiper JL, Djedovic V, Cozma AI, Ha V, Jayalath VH, Jenkins DJ, Meija SB, de Souza RJ, Jovanovski E, Vuksan V (2014) The effect of ginseng (the genus panax) on glycemic control: a systematic review and meta-analysis of randomized controlled clinical trials. PLoS One 9:e107391CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Mollah ML, Kim GS, Moon HK, Chung SK, Cheon YP, Kim JK, Kim KS (2009) Antiobesity effects of wild ginseng (Panax ginseng C.A. Meyer) mediated by PPAR-γ, GLUT4 and LPL in ob/ob mice. Phytother Res 23:220–225CrossRefPubMedGoogle Scholar
  12. 12.
    Mu Q, Fang X, Li X, Zhao D, Mo F, Jiang G, Yu N, Zhang Y, Guo Y, Fu M, Liu JL, Zhang D, Gao S (2015) Ginsenoside Rb1 promotes browning through regulation of PPARγ in 3T3-L1 adipocytes. Biochem Biophys Res Commun 466:530–535CrossRefPubMedGoogle Scholar
  13. 13.
    Suzuki T, Yamamoto A, Ohsawa M, Motoo Y, Mizukami H, Makino T (2015) Ninjin’yoeito and ginseng extract prevent oxaliplatin-induced neurodegeneration in PC12 cells. J Nat Med 69:531–537CrossRefPubMedGoogle Scholar
  14. 14.
    Shen H, Leung WI, Ruan JQ, Li SL, Lei JP, Wang YT, Yan R (2013) Biotransformation of ginsenoside Rb1 via the gypenoside pathway by human gut bacteria. Chin Med 8:22CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Niu T, Smith DL, Yang Z, Gao S, Yin T, Jiang ZH, You M, Gibbs RA, Petrosino JF, Hu M (2013) Bioactivity and bioavailability of ginsenosides are dependent on the glycosidase activities of the A/J mouse intestinal microbiome defined by pyrosequencing. Pharm Res 30:836–846CrossRefPubMedGoogle Scholar
  16. 16.
    Xiong J, Sun M, Guo J, Huang L, Wang S, Meng B, Ping Q (2009) Enhancement by adrenaline of ginsenoside Rg1 transport in Caco-2 cells and oral absorption in rats. J Pharm Pharmacol 61:347–352CrossRefPubMedGoogle Scholar
  17. 17.
    Chang TC, Huang SF, Yang TC, Chan FN, Lin HC, Chang WL (2007) Effect of ginsenosides on glucose uptake in human Caco-2 cells is mediated through altered Na+/glucose cotransporter 1 expression. J Agric Food Chem 55:1993–1998CrossRefPubMedGoogle Scholar
  18. 18.
    Han M, Fang XL (2006) Difference in oral absorption of ginsenoside Rg1 between in vitro and in vivo models. Acta Pharmacol Sin 27:499–505CrossRefPubMedGoogle Scholar
  19. 19.
    Brunet JL, Maresca M, Fantini J, Belzunces LP (2004) Human intestinal absorption of imidacloprid with Caco-2 cells as enterocyte model. Toxicol Appl Pharmacol 194:1–9CrossRefPubMedGoogle Scholar
  20. 20.
    Jiang S, Ren D, Li J, Yuan G, Li H, Xu G, Han X, Du P, An L (2014) Effects of compound K on hyperglycemia and insulin resistance in rats with type 2 diabetes mellitus. Fitoterapia 95:58–64CrossRefPubMedGoogle Scholar
  21. 21.
    Wang CW, Su SC, Huang SF, Huang YC, Chan FN, Kuo YH, Hung MW, Lin HC, Chang WL, Chang TC (2015) An essential role of cAMP response element binding protein in ginsenoside Rg1-mediated inhibition of Na+/glucose cotransporter 1 gene expression. Mol Pharmacol 88:1072–1083CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan 2016

Authors and Affiliations

  • Shengli Gao
    • 1
  • Hirotaka Kushida
    • 2
  • Toshiaki Makino
    • 1
  1. 1.Department of Pharmacognosy, Graduate School of Pharmaceutical SciencesNagoya City UniversityNagoyaJapan
  2. 2.Tsumura Research Laboratories, Kampo Scientific Strategies DivisionTsumura & Co.IbarakiJapan

Personalised recommendations