Skip to main content

Advertisement

Log in

Increased Transport of Resveratrol Across Monolayers of the Human Intestinal Caco-2 Cells is Mediated by Inhibition and Saturation of Metabolites

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The study's aim was to investigate the dose-dependent effect of sulfation and glucuronidation on intestinal absorption of resveratrol, a dietary constituent found in grapes and various medical plants.

Materials and Methods

The intestinal epithelial membrane transport kinetics and metabolism of resveratrol (10–200 μM) was studied using Caco-2 monolayers cultured in Transwells.

Results

Along with resveratrol it was possible to identify three metabolites, namely, resveratrol-4′-O-glucuronide (M1), resveratrol 3-O-gucuronide (M2), and resveratrol-3-O-sulfate (M3) by LC/MS and NMR. Efflux of the glucuronides M1 and M2 followed Michaelis–Menten kinetics significantly favouring basolateral efflux. The predominant metabolite was the monosulfate M3, however, its formation was strongly inhibited at higher resveratrol concentrations. As biotransformation was either inhibited or saturated, total amount of resveratrol transported across the Caco-2 monolayers increased as much as 3.5-fold at 200 μM resveratrol. This value might be even higher when taking into account the high intracellular concentration of resveratrol, which accounted for up to 61% of the applied dose.

Conclusions

Our data demonstrate a concentration-dependent biotransformation of resveratrol in Caco-2 cells, which may also apply to human enterocytes affecting oral bioavailability.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AP:

apical

BL:

basolateral

Cl i :

intrinsic clearance

HPLC:

high pressure liquid chromatography

K i :

inhibition constant

K m :

Michaelis constant

MRP:

multidrug resistance protein

P app :

permeability coefficient

P-gp:

P-glycoprotein

TEER:

transepithelial electrical resistance

V max :

maximal secretion rate

References

  1. J. Burns, T. Yokota, H. Ashihara, M. E. Lean, and A. Crozier. Plant foods and herbal sources of resveratrol. J. Agric. Food Chem. 50:3337–3340 (2002).

    Article  PubMed  CAS  Google Scholar 

  2. L. Frémont. Biological effects of Resveratrol. Life Sci. 66:663–673 (2000).

    Article  PubMed  Google Scholar 

  3. M. Jang and J. M. Pezzuto. Cancer chemopreventive activity of resveratrol. Drugs Exp. Clin.Res. 25:65–77 (1999).

    PubMed  CAS  Google Scholar 

  4. Y. J. Cai, J. G. Fang, L. P. Ma, L. Yang L, and Z. L. Liu. Inhibition of free radical-induced peroxidation of rat liver microsomes by resveratrol and its analogues. Biochim. Biophys. Acta 1637:31–38 (2003).

    PubMed  CAS  Google Scholar 

  5. B. Tadolini, C. Juliano, L. Piu, F. Franconi, and L. Cabrini. Resveratrol inhibition of lipid peroxidation. Free Radic. Res. 33:105–114 (2000).

    Article  PubMed  CAS  Google Scholar 

  6. P. Brito, L. M. Almeida, and T. C. Dinis. The interaction of resveratrol with ferrylmyoglobin and peroxynitrite; protection against LDL oxidation. Free Radic. Res. 36:621–631 (2002).

    Article  PubMed  CAS  Google Scholar 

  7. D. Pietraforte, L. Turco, E. Azzini, and M. Minetti. On-line EPR study of free radicals induced by peroxidase/H2O2 in human low-density lipoprotein. Biochim. Biophys. Acta 1583:176–184 (2002).

    PubMed  CAS  Google Scholar 

  8. S. Bradamante, L. Barenghi, F. Piccinini, A. A. Bertelli, R. De Jonge, P. Beemster, and J. W. De Jong. Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. Eur. J. Pharmacol. 465:115–123 (2003).

    Article  PubMed  CAS  Google Scholar 

  9. S. Shigematsu, S. Ishida, M. Hara, N. Takahashi, H. Yoshimatsu, T. Sakata T, and R. J. Korthuis. Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants. Free Radic Biol. Med. 34:810–817 (2003).

    Article  PubMed  CAS  Google Scholar 

  10. L. M. Hung, M. J. Su, W. K. Chu, C. W. Chiao, W. F. Chan, and J. K. Chen. The protective effect of resveratrols on ischaemia-reperfusion injuries of rat hearts is correlated with antioxidant efficacy. Br. J. Pharmacol. 135:1627–1633 (2002).

    Article  PubMed  CAS  Google Scholar 

  11. S. Renaud and M. de Lorgeril. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339: 523–1526 (1992).

    Article  Google Scholar 

  12. C. Yu, Y. G. Shin, A. Chow, Y. Li, J. W. Kosmeder, Y. S. Lee, W. H. Hirschelman, J. M. Pezzuto, R. G. Mehta, and R. B. van Breemen. Human, rat, and mouse metabolism of resveratrol. Pharm. Res. 19:1907–1914 (2002).

    Article  PubMed  CAS  Google Scholar 

  13. A. J. Gescher and W. P. Steward. Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer Epidemiol. Biomark. Prev. 12:953–957 (2003).

    CAS  Google Scholar 

  14. D. M. Goldberg, J. Yan, and G. J. Soleas. Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clin. Biochem. 36:79–87 (2003).

    Article  PubMed  CAS  Google Scholar 

  15. T. Walle, F. Hsieh, M. H. DeLegge, J. E. Oatis Jr., and U.K. Walle. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos. 12:1377–1382 (2004).

    Article  Google Scholar 

  16. X. Meng, P. Maliakal, H. Lu, M. J. Lee, and C. S. Yang. Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. J. Agric. Food Chem. 52:935–942 (2004).

    Article  PubMed  CAS  Google Scholar 

  17. C. De Santi, A. Pietrabissa, R. Spisni, F. Mosca, and G. M. Pacifici. Sulphation of resveratrol, a natural compound present in wine, and its inhibition by natural flavonoids. Xenobiotica 30:857–866 (2000).

    Article  PubMed  Google Scholar 

  18. M. I. Kaldas, U. K. Walle, and T. Walle. Resveratrol transport and metabolism by human intestinal Caco-2 cells. J. Pharm. Pharmacol. 55:307–312 (2003).

    Article  PubMed  CAS  Google Scholar 

  19. W. Jager, O. Winter, B. Halper, A. Salamon, M. Sartori, L. Gajdzik, G. Hamilton, G. Theyer, J. Graf, and T. Thalhammer. Modulation of liver canalicular transport processes by the tyrosine-kinase inhibitor genistein: implications of genistein metabolism in the rat. Hepatology 26:1467–1476 (1997).

    Article  PubMed  CAS  Google Scholar 

  20. Y. Li, Y. G. Shin, C. Yu, J. W. Kosmeder, W. H. Hirschelman, J. M. Pezzuto, and R. B. van Breemen. Increasing the throughput and productivity of Caco-2 cell permeability assays using liquid chromatography–mass spectrometry: application to resveratrol absorption and metabolism. Comb. Chem. High Throughput Screen. 6:757–767 (2003).

    PubMed  CAS  Google Scholar 

  21. S. Yee. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man-fact or myth. Pharm. Res. 14:763–766 (1997).

    Article  PubMed  CAS  Google Scholar 

  22. P. Artursson and J. Karlsson. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Commun. 175:880–885 (1991).

    Article  PubMed  CAS  Google Scholar 

  23. C. Henry, X. Vitrac, A. Decendit, R. Ennamany, S. Krisa, and J. M. Merillon. Cellular uptake and efflux of trans-piceid and its aglycone trans-resveratrol on the apical membrane of human intestinal Caco-2 cells. J. Agric. Food Chem. 53:798–803 (2005).

    Article  PubMed  CAS  Google Scholar 

  24. B. Jannin, M. Menzel, J. P. Berlot, D. Delmas, A. Lancon, and N. Latruffe. Transport of resveratrol, a cancer chemopreventive agent, to cellular targets: plasmatic protein binding and cell uptake. Biochem. Pharmacol. 68:1113–1118 (2004).

    Article  PubMed  CAS  Google Scholar 

  25. X. Vitrac, A. Desmouliere, B. Brouillaud, S. Krisa, G. Deffieux, N. Barthe, J. Rosenbaum, and J. M. Merillon. Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life Sci. 72:2219–2233 (2003).

    Article  PubMed  CAS  Google Scholar 

  26. V. Aumont, S. Krisa, E. Battaglia, P. Netter, T. Richard, J. M. Merillon, J. Magdalou, and N. Sabolovic. Regioselective and stereospecific glucuronidation of trans- and cis-resveratrol in human. Arch. Biochem. Biophys. 393:281–289 (2001).

    Article  PubMed  CAS  Google Scholar 

  27. M. Miksits, A. Maier-Salamon, S. Aust, T. Thalhammer, G, Resnicek, O. Kunert, E. Haslinger, T. Szekeres, and W. Jäger. Sulfation of resveratrol in human liver: evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1. Xenobiotica 35:1101–1119 (2005).

    Article  PubMed  CAS  Google Scholar 

  28. Y. Otake, A. L. Nolan, U. K. Walle, and T. Walle. Quercetin and resveratrol potently reduce estrogen sulfotransferase activity in normal human mammary epithelial cells. J. Steroid Biochem. Mol. Biol. 73:265–270 (2000).

    Article  PubMed  CAS  Google Scholar 

  29. J. R. Pasqualini and G. S. Chetrite. Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. J Steroid Biochem Mol Biol. 93:221–236 (2005).

    Article  PubMed  CAS  Google Scholar 

  30. G. Regev-Shoshani, O. Shoseyov, I. Bilkis, and Z. Kerem. Glycosylation of resveratrol protects it from enzymic oxidation. Biochem. J. 374:157–163 (2003).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant from the Jubiläumsfonds der Österreichischen Nationalbank 9894 (W.J.) and by the Fonds zur Förderung der Wissenschaftlichen Forschung des Bürgermeisters der Bundeshauptstadt Wien (2296; T.S.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Walter Jäger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maier-Salamon, A., Hagenauer, B., Wirth, M. et al. Increased Transport of Resveratrol Across Monolayers of the Human Intestinal Caco-2 Cells is Mediated by Inhibition and Saturation of Metabolites. Pharm Res 23, 2107–2115 (2006). https://doi.org/10.1007/s11095-006-9060-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-006-9060-z

Key words

Navigation