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Pharmaceutical Research

, Volume 19, Issue 12, pp 1907–1914 | Cite as

Human, Rat, and Mouse Metabolism of Resveratrol

  • Chongwoo Yu
  • Young Geun Shin
  • Anita Chow
  • Yongmei Li
  • Jerome W. Kosmeder
  • Yong Sup Lee
  • Wendy H. Hirschelman
  • John M. Pezzuto
  • Rajendra G. Mehta
  • Richard B. van Breemen
Article

Abstract

Purpose. Resveratrol, a phenolic phytoalexin occurring in grapes, wine, peanuts, and cranberries, has been reported to have anticarcinogenic, antioxidative, phytoestrogenic, and cardioprotective activities. Because little is known about the metabolism of this potentially important compound, the in vitro and in vivo metabolism of trans-resveratrol were investigated.

Methods. The in vitro experiments included incubation with human liver microsomes, human hepatocytes, and rat hepatocytes and the in vivo studies included oral or intraperitoneal administration of resveratrol to rats and mice. Methanol extracts of rat urine, mouse serum, human hepatocytes, rat hepatocytes, and human liver microsomes were analyzed for resveratrol metabolites using reversed-phase high-performance liquid chromatography with on-line ultraviolet-photodiode array detection and mass spectrometric detection (LC-DAD-MS and LC-UV-MS-MS). UV-photodiode array analysis facilitated the identification of cis- and trans-isomers of resveratrol and its metabolites. Negative ion electrospray mass spectrometric analysis provided molecular weight confirmation of resveratrol metabolites and tandem mass spectrometry allowed structural information to be obtained.

Results. No resveratrol metabolites were detected in the microsomal incubations, and no phase I metabolites, such as oxidations, reductions, or hydrolyzes, were observed in any samples. However, abundant trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate were identified in rat urine, mouse serum, and incubations with rat and human hepatocytes. Incubation with β-glucuronidase and sulfatase to release free resveratrol was used to confirm the structures of these conjugates. Only trace amounts of cis-resveratrol were detected, indicating that isomerization was not an important factor in the metabolism and elimination of resveratrol.

Conclusion. Our results indicate that trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate are the most abundant metabolites of resveratrol. Virtually no unconjugated resveratrol was detected in urine or serum samples, which might have implications regarding the significance of in vitro studies that used only unconjugated resveratrol.

trans-resveratrol metabolism LC-MS-MS glucuronides sulfates 

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REFERENCES

  1. 1.
    M. B. Sporn, N. M. Dunlop, D. L. Newton, and J. M. Smith. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed. Proc. 35:1332–1338 (1976).Google Scholar
  2. 2.
    W. K. Hong and M. B. Sporn. Recent advances in chemoprevention of cancer. Science 278:1073–1074 (1997).Google Scholar
  3. 3.
    M. Jang, L. Cai, G. O. Udeani, K. V. Slowing, C. F. Thomas, C. W. W. Beecher, H. H. S. Fong, N. R. Farnsworth, A. D. Kinghorn, R. G. Mehta, R. C. Moon, and J. M. Pezzuto. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220 (1997).Google Scholar
  4. 4.
    M. Jang and J. M. Pezzuto. Cancer chemopreventive activity of resveratrol. Drugs Exp. Clin. Res 25:65–77 (1999).Google Scholar
  5. 5.
    J. A. Bailey. Mechanism of phytoalexin accumulation. In Phytoalexins, eds. J. A. Baily and J. W. Manfield, pp. 289–318, Wiley, New York, 1982.Google Scholar
  6. 6.
    Y. Wang, F. Catana, Y. Yang, R. Roderick, and R. B. van Breemen. Analysis of resveratrol in grape products, cranberry juice and wine using liquid chromatography-mass spectrometry. J. Agric. Food Chem. 50:431–435 (2002).Google Scholar
  7. 7.
    E. N. Frankel, A. L. Waterhouse, and J. E. Kinsella. Inhibition of human LDL oxidation by resveratrol. Lancet 341:1103–1104 (1993).Google Scholar
  8. 8.
    N. J. Miller and C. A. Rice-Evans. Antioxidant activity of resveratrol in red wine-to the editor. Clin. Chem. 41:1789 (1995).Google Scholar
  9. 9.
    B. Fuhrman, A. Lavy, and M. Aviram. Consumption of red wine with meals reduces the susceptibility of human plasma and lowdensity-lipoprotein to lipid-peroxidation. Am. J. Clin. Nutr. 42: 549–554 (1995).Google Scholar
  10. 10.
    A. A. E. Bertelli, L. Giovannini, D. Giannesi, M. Migliori, W. Bernini, M. Fregoni, and A. Bertelli. Antiplatelet activity of synthetic and natural resveratrol in red wine. Int. J. Tissue React. 17:1–3 (1995).Google Scholar
  11. 11.
    C. R. Pace-Asciak, S. E. Hahn, E. P. Diamandis, G. Soleas, and D. M. Goldberg. The red wine phenolics trans-resveratrol and quercetin block human platelet-aggregation and eicosanoid synthesis-Implications for protection against coronary heartdisease. Clin. Chim. Acta 235:207–219 (1995).Google Scholar
  12. 12.
    Y. Kimura, H. Okuda, and S. Arichi. Effects of stilbenes on arachidonate metabolism in leukocytes. Biochim. Biophys. Acta 834: 275–278 (1985).Google Scholar
  13. 13.
    S. Sotheeswaran and V. Pasupathy. Distribution of resveratrol oligomers in plants. Phtyochemistry 32:1083–1092 (1993).Google Scholar
  14. 14.
    P. Kopp. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the “French paradox”? Eur. J. Endocrinol. 138:619–620 (1998).Google Scholar
  15. 15.
    R. Lu and G. Serrero. Resveratrol, a natural product derived from grape exhibits antiestrogenic activity and inhibits the growth of the human breast cancer cells. J. Cell Physiol. 179:297–304 (1999).Google Scholar
  16. 16.
    D. K. Das, M. Sato, P. S. Ray, G. Maulik, R. M. Engelman. A. A. E. Bertelli, A. Bertelli. Cardioprotection of red wine: Role of polyphenolic antioxidants. Drugs Exptl. Clin. Res. 25:115–120 (1999).Google Scholar
  17. 17.
    C. R. Pace-Asciak, O. Rounova, S. E. Hahn, E. P. Diamandis, and D. M. Goldberg. Wines and grape juices as modulation of platelet aggregation in healthy human subjects. Clin. Chim. Acta. 246:163–182 (1996).Google Scholar
  18. 18.
    A. A. E. Bertelli, L. Giovannini, R. Stradi, S. Urien, J.-P. Tillement, and A. Bertelli. Kinetics of trans-and cis-resveratrol (3,4',5-trihydroxystilbene) after red wine oral administration in rats. Int. J. Clin. Pharm. Res. 16:77–81 (1996).Google Scholar
  19. 19.
    W. Andlauer, J. Kolb, K. Siebert, and P. Fürst. Assessment of resveratrol bioavailability in the perfused small intestine of the rat. Drugs Exptl. Clin. Res. 26:47–55 (2000).Google Scholar
  20. 20.
    G. Kuhnle, J. P. Spencer, G. Chowrimootoo, H. Schroeter, E. S. Debnam, S. K. S. Srai, C. Rice-Evans, and U. Hahn. Resveratrol is absorbed in the small intestine as resveratrol glucuronide. Biochem. Biophys. Res. Commun. 272:212–217 (2000).Google Scholar
  21. 21.
    C. De Santi, A. Pietrabissa, R. Spisni, F. Mosca, and G. M. Pacifici. Sulphation of resveratrol, a natural product present in grapes and wine, in human liver and duodenum. Xenobiotica 30:609–617 (2000).Google Scholar
  22. 22.
    C. De Santi, A. Pietrabissa, R. Spisni, F. Mosca, and G. M. Pacifici. Sulphation of resveratrol, a natural product present in wine, and its inhibition by natural flavonoids. Xenobiotica 30:857–866 (2000).Google Scholar
  23. 23.
    C. De Santi, A. Pietrabissa, F. Mosca, and G. M. Pacifici. Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liver. Xenobiotica 30:1047–1054 (2000).Google Scholar
  24. 24.
    A. P. Li, C. Lu, J. A. Brent, C. Pham, A. Fackett, C. E. Ruegg, and P. M. Silber. Cryopreserved human hepatocytes: characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential. Chem. Biol. Interact. 121:17–35 (1999).Google Scholar
  25. 25.
    A. P. Li. Overview: Hepatocytes and cryopreservation-a personal historical perspective. Chem. Biol. Interact. 121:1–5 (1999).Google Scholar
  26. 26.
    J. Sfakianos, L. Coward, M. Kirk, and S. Barnes. Intestinal uptake and biliary excretion of the isoflavones genistein in rats. J. Nutr. 127:1260–1268 (1997).Google Scholar
  27. 27.
    N. Kawai, Y. Fujibayashi, S. Kuwabara, K.-I. Takao, Y. Ijuin, and S. Kobayashi. Synthesis of a potential key intermediate of akaterpin, specific inhibitor of PI-PLC. Tetrahedron 56:6467–6478 (2000).Google Scholar
  28. 28.
    L. Debrauwer, E. Rathahao, G. Boudry, M. Baradat, and J. P. Cravedi. Identification of major metabolites of prochloraz in rainbow trout by liquid chromatography and tandem mass spectrometry. J. Agric. Food Chem. 49:3821–3826 (2001).Google Scholar
  29. 29.
    P. Manini, R. Andreoli, A. Mutti, E. Bergamaschi, I. Franchini, and W. M. A. Niessen. Determination of glucuronide molecules of toxicological interest by liquid chromatography negative-ion mass spectrometry with atmospheric pressure chemical ionization. Chromatographia 47:659–666 (1998).Google Scholar
  30. 30.
    D. M. Goldberg, E. Ng, A. Karumanchiri, J. Yan, E. P. Diamandis, and G. J. Soleas. Assay of resveratrol glycosides and isomers in wine by direct-injection high-performance liquid chromatography. J. Chromatogr. A 708:89–98 (1995).Google Scholar
  31. 31.
    B. C. Trela and A. L. Waterhouse. Resveratrol: Isomeric molar absorptivities and stability. J. Agric. Food Chem. 44:1253–1257 (1996).Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Chongwoo Yu
    • 1
    • 2
  • Young Geun Shin
    • 1
  • Anita Chow
    • 3
  • Yongmei Li
    • 1
  • Jerome W. Kosmeder
    • 1
  • Yong Sup Lee
    • 2
  • Wendy H. Hirschelman
    • 2
  • John M. Pezzuto
    • 1
  • Rajendra G. Mehta
    • 3
  • Richard B. van Breemen
    • 1
  1. 1.Department of Medicinal Chemistry and PharmacognosyUniversity of Illinois at ChicagoChicago
  2. 2.Department of ChemistryUniversity of Illinois at ChicagoChicago
  3. 3.Department of Surgical OncologyUniversity of Illinois at ChicagoChicago

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