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

Toxicology and Metabolism, Biosciences Division, SRI International, Menlo Park, California (A.M.F., C.E.G., L.E.H.S., P.C., T.P., L.V.I.); Department of Pharmacology and Therapeutics, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota (A.A.A); Chemopreventive Agent Development Research Group, Roswell Park Cancer Institute, Buffalo, New York (I.M.K.); and Division of Clinical Pharmacology, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland (R.M.W.)

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 17β-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 µM) 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 K_i values of 1.1 µM (liver), 0.6 µM (jejunum), and 2.3 µM (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.