Trans-resveratrol, a well-known plant phenolic compound, has been intensively investigated due to its association with the so-called French paradox. However, despite its high pharmacological potential, trans-resveratrol has shown relatively low bioavailability. Trans-resveratrol is intensively metabolized in the intestine and liver, yielding metabolites that may be responsible for its high bioactivity. The aim of this study was to investigate and compare the metabolism of trans-resveratrol (tRes), cis-resveratrol (cRes) and dihydroresveratrol (dhRes) in an in vitro epithelial model using Caco-2 cell lines. Obtained metabolites of tRes, cRes and dhRes were analyzed by LC/MS Q-TOF, and significant differences in the metabolism of each compound were observed. The majority of tRes was transported unchanged through the Caco-2 cells, while cRes was mostly metabolized. The main metabolite of both cis- and trans-resveratrol observed as a result of colon microbial metabolism, dhRes, was metabolized almost completely, with only traces of the unchanged molecule being found. A sulphate conjugate was identified as the main metabolite of tRes in our model, while a glucuronide conjugate was the major metabolite of cRes and dhRes. Since metabolism of simple phenolics and polyphenols plays a crucial role in their bioavailability, detailed knowledge of their transformation is of high scientific value.

Department of Food Science The Faculty of Agrobiology Food and Natural Resources The Czech University of Life Sciences Prague 16500 Prague Czech Republic

Department of Microbiology Nutrition and Dietetics The Faculty of Agrobiology Food and Natural Resources Czech University of Life Sciences Prague 16500 Prague Czech Republic

Department of Natural Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno 61242 Brno Czech Republic

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El Khawand T., Courtois A., Valls J., Richard T., Krisa S. A review of dietary stilbenes: sources and bioavailability. Phytochem. Rev. 2018;17:1007–1029. doi: 10.1007/s11101-018-9578-9. DOI

Berman A.Y., Motechin R.A., Wiesenfeld M.Y., Holz M.K. The therapeutic potential of resveratrol: a review of clinical trials. NPJ Precis. Oncol. 2017;35:1–9. doi: 10.1038/s41698-017-0038-6. PubMed DOI PMC

Moreno A., Castro M., Falqué E. Evolution of trans- and cis-resveratrol content in red grapes (Vitis vinifera L. cv Mencía, Albarello and Merenzao) during ripening. Eur. Food Res. Technol. 2008;227:667–674. doi: 10.1007/s00217-007-0770-1. DOI

Renaud S., de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet. 1992;339:1523–1526. doi: 10.1016/0140-6736(92)91277-F. PubMed DOI

Kopp P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the’French paradox’? Eur. J. Endocrinol. 1998;138:619–620. doi: 10.1530/eje.0.1380619. PubMed DOI

Walle T., Hsieh F., DeLegge M.H., Oatis J.E., Walle U.K. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos. 2004;32:1377–1382. doi: 10.1124/dmd.104.000885. PubMed DOI

Wenzel E., Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol. Nutr. Food Res. 2005;49:472–481. doi: 10.1002/mnfr.200500010. PubMed DOI

Jarosova V., Vesely O., Marsik P., Jaimes J.D., Smejkal K., Kloucek P., Havlik J. Metabolism of stilbenoids by human faecal microbiota. Molecules. 2019;24:1155. doi: 10.3390/molecules24061155. PubMed DOI PMC

Bode L.M., Bunzel D., Huch M., Cho G.S., Ruhland D., Bunzel M., Bub A., Franz C.M., Kulling S.E. In vivo and in vitro metabolism of trans-resveratrol by human gut microbiota. Am. J. Clin. Nutr. 2013;97:295. doi: 10.3945/ajcn.112.049379. PubMed DOI

Juan M.E., González-Pons E., Planas J.M. Multidrug Resistance Proteins Restrain the Intestinal Absorption of trans-Resveratrol in Rats. J. Nutr. 2010;140:489–495. doi: 10.3945/jn.109.114959. PubMed DOI

Maier-Salamon A., Hagenauer B., Wirth M., Gabor F., Szekeres T., Jäger W. Increased transport of resveratrol across monolayers of the human intestinal Caco-2 cells is mediated by inhibition and saturation of metabolites. Pharm. Res. 2006;23:2107–2115. doi: 10.1007/s11095-006-9060-z. PubMed DOI

Urpi-Sarda M., Zamora-Ros R., Lamuela-Raventos R., Cherubini A., Jauregui O., De La Torre R., Covas M.I., Estruch R., Jaeger W., Andres-Lacueva C. HPLC-Tandem Mass Spectrometric Method to Characterize Resveratrol Metabolism in Humans. Clin. Chem. 2007;53:292–299. doi: 10.1373/clinchem.2006.071936. PubMed DOI

Boocock D.J., Faust G.E.S., Patel K.R., Schinas A.M., Brown V.A., Ducharme M.P., Booth T.D., Crowell J.A., Perloff M., Gescher A.J., et al. Phase I Dose Escalation Pharmacokinetic Study in Healthy Volunteers of Resveratrol, a Potential Cancer Chemopreventive Agent. Cancer Epidemiol. Biomarkers Prev. 2007;16:1246–1252. doi: 10.1158/1055-9965.EPI-07-0022. PubMed DOI

Chen M., Yi L., Jin X., Xie Q., Zhang T., Zhou X., Chang H., Fu Y., Zhu J., Zhang Q., et al. Absorption of resveratrol by vascular endothelial cells through passive diffusion and an SGLT1-mediated pathway. J. Nutr. Biochem. 2013;24:1823–1829. doi: 10.1016/j.jnutbio.2013.04.003. PubMed DOI

Maier-Salamon A., Böhmdorfer M., Riha J., Thalhammer T., Szekeres T., Jaeger W. Interplay between metabolism and transport of resveratrol. Ann. N. Y. Acad. Sci. 2013;1290:98–106. doi: 10.1111/nyas.12198. PubMed DOI

Lagouge M., Argmann C., Gerhart-Hines Z., Meziane H., Lerin C., Daussin F., Messadeq N., Milne J., Lambert P., Elliott P., et al. Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α. Cell. 2006;127:1109–1122. doi: 10.1016/j.cell.2006.11.013. PubMed DOI

Timmers S., Konings E., Bilet L., Houtkooper R.H., van de Weijer T., Goossens G.H., Hoeks J., van der Krieken S., Ryu D., Kersten S., et al. Calorie Restriction-like Effects of 30 Days of Resveratrol Supplementation on Energy Metabolism and Metabolic Profile in Obese Humans. Cell Metab. 2011;14:612–622. doi: 10.1016/j.cmet.2011.10.002. PubMed DOI PMC

Falomir E., Lucas R., Peñalver P., Martí-Centelles R., Dupont A., Zafra-Gómez A., Carda M., Morales J.C. Cytotoxic, Antiangiogenic and Antitelomerase Activity of Glucosyl- and Acyl- Resveratrol Prodrugs and Resveratrol Sulfate Metabolites. ChemBioChem. 2016;17:1343–1348. doi: 10.1002/cbic.201600084. PubMed DOI

Storniolo C.E., Quifer-Rada P., Lamuela-Raventos R.M., Moreno J.J. Piceid presents antiproliferative effects in intestinal epithelial Caco-2 cells, effects unrelated to resveratrol release. Food Funct. 2014;5:2137–2144. doi: 10.1039/C4FO00305E. PubMed DOI

Su D., Cheng Y., Liu M., Liu D., Cui H., Zhang B., Zhou S., Yang T., Mei Q. Comparision of Piceid and Resveratrol in Antioxidation and Antiproliferation Activities In Vitro. PLoS ONE. 2013;8:e54505. doi: 10.1371/journal.pone.0054505. PubMed DOI PMC

Jarosova V., Doskocil I., Volstatova T., Havlik J. Adhesive Property of Different Strains of Lactobacilli in the Presence of Resveratrol. Sci. Agric. Bohem. 2018;49:291–296. doi: 10.2478/sab-2018-0036. DOI

Hubatsch I., Ragnarsson E.G.E., Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat. Protoc. 2007;2:2111–2119. doi: 10.1038/nprot.2007.303. PubMed DOI

Li Y., Shin Y., Yu C., Kosmeder J., Hirschelman W., Pezzuto J., van Breemen R. 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. 2012;6:757–767. doi: 10.2174/138620703771826865. PubMed DOI

Henry C., Vitrac X., Decendit A., Ennamany R., Krisa S., Mérillon J.M. 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. 2005;53:798–803. doi: 10.1021/jf048909e. PubMed DOI

Kaldas M.I., Walle U.K., Walle T. Resveratrol transport and metabolism by human intestinal Caco-2 cells. J. Pharm. Pharmacol. 2003;55:307–312. doi: 10.1211/002235702612. PubMed DOI

Kuhnle G., Spencer J.P.E., Chowrimootoo G., Schroeter H., Debnam E.S., Srai S.K.S., Rice-Evans C., Hahn U. Resveratrol is absorbed in the small intestine as resveratrol glucuronide. Biochem. Biophys. Res. Commun. 2000;272:212–217. doi: 10.1006/bbrc.2000.2750. PubMed DOI

Azorín-Ortuño M., Yáñez-Gascón M.J., Vallejo F., Pallarés F.J., Larrosa M., Lucas R., Morales J.C., Tomás-Barberán F.A., García-Conesa M.T., Espín J.C. Metabolites and tissue distribution of resveratrol in the pig. Mol. Nutr. Food Res. 2011;55:1154–1168. doi: 10.1002/mnfr.201100140. PubMed DOI

Sabolovic N., Humbert A.C., Radominska-Pandya A., Magdalou J. Resveratrol is efficiently glucuronidated by UDP-glucuronosyltransferases in the human gastrointestinal tract and in Caco-2 cells. Biopharm. Drug Dispos. 2006;27:181–189. doi: 10.1002/bdd.498. PubMed DOI

Juan M.E., Alfaras I., Planas J.M. Determination of dihydroresveratrol in rat plasma by HPLC. J. Agric. Food Chem. 2010;58:7472–7475. doi: 10.1021/jf100836j. PubMed DOI

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