Effect of Resveratrol on 17 -Estradiol Sulfation by Human Hepatic and Jejunal S9 and Recombinant Sulfotransferase 1E1

The purpose of this study was to investigate the sulfation of resveratrol (3,5,4 -trihydroxystilbene) and its potential to exhibit drug-drug interactions via sulfation. The possible interaction of resveratrol with 17 -estradiol (E2), a major estrogen hormone and prototypic substrate for sulfate conjugation, was studied. Resveratrol and E2 are both known to undergo sulfate conjugation catalyzed by human sulfotransferases (SULTs). Resveratrol is a phytoestrogen with mixed estrogen agonist/antagonist properties that is being developed as a chemopreventive agent. The sulfate conjugation of E2 and resveratrol were studied individually using S9 fractions from human liver and jejunum as well as recombinant human SULT isoforms. The sulfation of E2 (3–20 nM) was then investigated in the presence of various concentrations (0, 0.5, 1, and 2 M) of resveratrol using the two S9 preparations as well as recombinant SULT1E1, the major isoform responsible for E2 sulfation. Resveratrol inhibited E2 sulfation with estimated Ki values of 1.1 M (liver), 0.6 M (jejunum), and 2.3 M (SULT1E1), concentrations that could be pharmacologically relevant. The results suggest that these phytoestrogens can potentially alter the homeostasis of estrogen levels. These findings also imply that resveratrol may inhibit the metabolism of other estrogen analogs or therapeutic agents such as ethinylestradiol or dietary components that are also substrates for SULT1E1. Resveratrol (trans-3,5,4 -trihydroxystilbene) (Fig. 1) is a polyphenolic phytoestrogen found in high concentrations in red wine (Kopp, 1998) and a variety of plant sources such as grape skin, berries, pomegranates, and peanuts. It has generated considerable research interest because it has a wide range of biological effects that include antioxidant, chemopreventive, cardioprotective, neuroprotective, antiinflammatory, and antiviral activity (Bhat et al., 2001; Aziz et al., 2003; Baur and Sinclair, 2006). Resveratrol has also been shown to have antiaging effects on the basis of recent reports of a significant improvement in health and lifespan after chronic administration of this phytoestrogen to mice fed with a high-calorie diet (Baur et al., 2006). The estrogenic potential of resveratrol is under active investigation. It has been shown to bind to estrogen receptors (ER and ER ) and appears to have antiestrogenic effects at high doses (Gehm et al., 1997). Recent studies have shown an induction of apoptosis and a reduction in extracellular levels of angiogenic vascular endothelial growth factor by resveratrol in human breast cancer xenografts (Garvin et al., 2006). The metabolism of resveratrol in humans involves sulfation and glucuronidation. The oral bioavailability of free resveratrol is low because of its rapid phase II conjugation to sulfates and glucuronides (Walle et al., 2004). Resveratrol 3-O-sulfate is the major reported sulfated metabolite of resveratrol in humans and rats, with other sulfate conjugates such as resveratrol 4 -sulfate, 3,5-disulfate, 3,4 -disulfate, and 3,4 ,5-trisulfate having been identified in in vivo studies (De Santi et al., 2000a,b; Walle et al., 2004; Wenzel and Somoza, 2005). SULT1A1 and SULT1E1 have been implicated in the sulfation of resveratrol (Miksits et al., 2005). Our previous work (Brill et al., 2006) as well as other studies (Aumont et al., 2001) have reported the roles of uridine diphosphate glucuronosyltransferase (UGT) isoforms 1A1 and 1A9 in the 3-O-glucuronidation and 4 -O-glucuronidation of trans-resveratrol, respectively. Piceatannol (3,3 , This study was supported by funds from the National Cancer Institute ((N01CN-43305; to C.E.G.), the National Institutes of General Medical Sciences (R01 GM35720 and U01 GM61388), The Pharmacogenetics Research Network (to A.A. and R.W.) and the PhRMA Foundation (A Center of Excellence in Clinical Pharmacology Award to R.W.). Preliminary results from this study were presented in “Inhibition of human hepatic and jejunal estradiol sulfation by resveratrol and piceatannol” (Furimsky AM, Sharp LE, Bettridge A, Kapetanovic IM, Green CE, Iyer LV) at Experimental Biology 2006 in San Francisco, CA, April 1–5, 2006. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.107.016725. ABBREVIATIONS: ER, estrogen receptor; SULT, sulfotransferase; UGT, uridine diphosphate glucuronosyltransferase; E2, 17 -estradiol; EST, estrogen sulfotransferase, SULT1E1; DTT, dithiothreitol; PAPS, adenosine 3 -phosphate 5 -phosphosulfate; BSA, bovine serum albumin; HPLC, high-performance liquid chromatography; PDA, photodiode array detector; LC, liquid chromatography; MS, mass spectrometry, MS/MS, tandem mass spectrometry. 0090-9556/08/3601-129–136 DRUG METABOLISM AND DISPOSITION Vol. 36, No. 1 U.S. Government work not protected by U.S. copyright 16725/3290010 DMD 36:129–136, 2008 Printed in U.S.A. 129 at A PE T Jornals on O cber 9, 2017 dm d.aspurnals.org D ow nladed from