Resveratrol has demonstrated cancer chemopreventive activity in animal models and some clinical trials are underway. In addition, resveratrol was shown to promote cell survival, increase lifespan and mimic caloric restriction, thereby improving health and survival of mice on high-calorie diet. All of these effects are potentially mediated by the pleiotropic interactions of resveratrol with different enzyme targets including COX-1 (cyclo-oxygenase-1) and COX-2, NAD+-dependent histone deacetylase SIRT1 (sirtuin 1) and QR2 (quinone reductase 2). Nonetheless, the health benefits elicited by resveratrol as a direct result of these interactions with molecular targets have been questioned, since it is rapidly and extensively metabolized to sulfate and glucuronide conjugates, resulting in low plasma concentrations. To help resolve these issues, we tested the ability of resveratrol and its metabolites to modulate the function of some known targets in vitro. In the present study, we have shown that COX-1, COX-2 and QR2 are potently inhibited by resveratrol, and that COX-1 and COX-2 are also inhibited by the resveratrol 4′-O-sulfate metabolite. We determined the X-ray structure of resveratrol bound to COX-1 and demonstrate that it occupies the COX active site similar to other NSAIDs (non-steroidal anti-inflammatory drugs). Finally, we have observed that resveratrol 3- and 4′-O-sulfate metabolites activate SIRT1 equipotently to resveratrol, but that activation is probably a substrate-dependent phenomenon with little in vivo relevance. Overall, the results of this study suggest that in vivo an interplay between resveratrol and its metabolites with different molecular targets may be responsible for the overall beneficial health effects previously attributed only to resveratrol itself.
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Research Article|
June 28 2010
Pleiotropic mechanisms facilitated by resveratrol and its metabolites
Barbara Calamini;
*Department of Medicinal Chemistry and Pharmacognosy and Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, U.S.A.
2Correspondence should be addressed to either of these authors (email b-calamini@northwestern.edu or mesecar@uic.edu).
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Kiira Ratia;
Kiira Ratia
*Department of Medicinal Chemistry and Pharmacognosy and Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, U.S.A.
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Michael G. Malkowski;
Michael G. Malkowski
†Hauptman-Woodward Medical Research Institute and Department of Structural Biology, State University of New York at Buffalo, Buffalo, NY 14203, U.S.A.
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Muriel Cuendet;
Muriel Cuendet
‡School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland
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John M. Pezzuto;
John M. Pezzuto
§College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI 96720, U.S.A.
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Bernard D. Santarsiero;
Bernard D. Santarsiero
*Department of Medicinal Chemistry and Pharmacognosy and Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, U.S.A.
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Andrew D. Mesecar
Andrew D. Mesecar
2
*Department of Medicinal Chemistry and Pharmacognosy and Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, U.S.A.
2Correspondence should be addressed to either of these authors (email b-calamini@northwestern.edu or mesecar@uic.edu).
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Publisher: Portland Press Ltd
Received:
December 07 2009
Revision Received:
April 20 2010
Accepted:
May 07 2010
Accepted Manuscript online:
May 07 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 429 (2): 273–282.
Article history
Received:
December 07 2009
Revision Received:
April 20 2010
Accepted:
May 07 2010
Accepted Manuscript online:
May 07 2010
Citation
Barbara Calamini, Kiira Ratia, Michael G. Malkowski, Muriel Cuendet, John M. Pezzuto, Bernard D. Santarsiero, Andrew D. Mesecar; Pleiotropic mechanisms facilitated by resveratrol and its metabolites. Biochem J 15 July 2010; 429 (2): 273–282. doi: https://doi.org/10.1042/BJ20091857
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