This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Harris, R. M. Articles by Kirk, C. J. Search for Related Content PubMed PubMed Citation Articles by Harris, R. M. Articles by Kirk, C. J.

Phytoestrogens Are Potent Inhibitors of Estrogen Sulfation: Implications for Breast Cancer Risk and Treatment

School of Biosciences and Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom

Address all correspondence and requests for reprints to: C. J. Kirk, School of Biosciences and Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. E-mail: c.j.kirk{at}bham.ac.uk.

We investigated the ability of 37 flavonoids and flavonoid sulfoconjugates, including some abundant dietary constituents, to act as substrates and/or inhibitors of the sulfotransferase and sulfatase enzymes that interconvert active estrogens and inactive estrogen sulfates in human tissues. The enzymes studied include estrogen sulfotransferase, the thermostable phenolsulfotransferase that acts on a range of substrates including estrogens; steroid sulfatase; and two related enzymes, monoamine phenolsulfotransferase and arylsulfatase A. Several dietary flavonoids, including the soy isoflavones genistein and daidzein, were sulfated by these human sulfotransferases. Many flavonoids were potent inhibitors of thermostable phenolsulfotransferase. Genistein and equol were potent mixed inhibitors of hepatic estrogen sulfotransferase, with inhibitory constant values of 500 nM and 400 nM, respectively. Monoamine phenolsulfotransferase activity was relatively unaffected by flavonoids, but this enzyme was mainly responsible for the sulfation of flavonoids at concentrations greater than 1 µM. Of the compounds tested, only daidzein 4,7-bisulfate, a trace metabolite in humans, significantly inhibited steroid sulfatase in the micromolar concentration range. Hence, dietary flavonoids may be able to influence the bioavailability of endogenous estrogens, and disrupt endocrine balance, by increasing the ratio of active estrogens to inactive estrogen sulfates in human tissues.

This work was supported by the Food Standards Agency (United Kingdom). P.J.H. is a Leukemia Research Fund Senior Fellow. D.M.W. and L.B. were the recipients of research studentships from the Medical Research Council (UK) and Biotechnology and Biological Sciences Research Council (UK), respectively.

Abbreviations: DMSO, Dimethylsulfoxide; E₁, estrone; E₁S, estrone sulfate; [³H]-E₁S, [6,7-³H(N)]-estrone sulfate; E₂, estradiol; K_i, inhibitory constant (active site); K_i, inhibitory constant (allosteric site); PAPS, adenosine 3'-phosphate 5'-phosphosulfate; SULT1A1, phenolsulfotransferase; SULT1A3, monoamine phenolsulfotransferase; SULT1E1, estrogen sulfotransferase.

This article has been cited by other articles:

				R. T. Paitz and R. M. Bowden A proposed role of the sulfotransferase/sulfatase pathway in modulating yolk steroid effects Integr. Comp. Biol., September 1, 2008; 48(3): 419 - 427. [Abstract] [Full Text] [PDF]

				C. J. Crandall, M. Guan, G. A. Laughlin, G. A. Ursin, F. Z. Stanczyk, S. A. Ingles, E. Barrett-Connor, and G. A. Greendale Increases in Serum Estrone Sulfate Level Are Associated with Increased Mammographic Density during Menopausal Hormone Therapy Cancer Epidemiol. Biomarkers Prev., July 1, 2008; 17(7): 1674 - 1681. [Abstract] [Full Text] [PDF]

				D Pugazhendhi, K A Watson, S Mills, N Botting, G S Pope, and P D Darbre Effect of sulphation on the oestrogen agonist activity of the phytoestrogens genistein and daidzein in MCF-7 human breast cancer cells J. Endocrinol., June 1, 2008; 197(3): 503 - 515. [Abstract] [Full Text] [PDF]

				D. Ung and S. Nagar Variable Sulfation of Dietary Polyphenols by Recombinant Human Sulfotransferase (SULT) 1A1 Genetic Variants and SULT1E1 Drug Metab. Dispos., May 1, 2007; 35(5): 740 - 746. [Abstract] [Full Text] [PDF]

				S. Rice and S. A Whitehead Phytoestrogens and breast cancer -promoters or protectors? Endocr. Relat. Cancer, December 1, 2006; 13(4): 995 - 1015. [Abstract] [Full Text] [PDF]

				R. Piller, E. Verla-Tebit, S. Wang-Gohrke, J. Linseisen, and J. Chang-Claude CYP17 Genotype Modifies the Association between Lignan Supply and Premenopausal Breast Cancer Risk in Humans J. Nutr., June 1, 2006; 136(6): 1596 - 1603. [Abstract] [Full Text] [PDF]

				F. M. Sacks, A. Lichtenstein, L. Van Horn, W. Harris, P. Kris-Etherton, M. Winston, and for the American Heart Association Nutrition Commi Soy Protein, Isoflavones, and Cardiovascular Health: An American Heart Association Science Advisory for Professionals From the Nutrition Committee Circulation, February 21, 2006; 113(7): 1034 - 1044. [Abstract] [Full Text] [PDF]

				C. Atkinson, C. L. Frankenfeld, and J. W. Lampe Gut Bacterial Metabolism of the Soy Isoflavone Daidzein: Exploring the Relevance to Human Health Experimental Biology and Medicine, March 1, 2005; 230(3): 155 - 170. [Abstract] [Full Text] [PDF]