Phytoestrogens are potent inhibitors of estrogen sulfation: implications for breast cancer risk and treatment.
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 micro M. 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.
Harris
R M
RM
School of Biosciences and Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Wood
D M
DM
Bottomley
L
L
Blagg
S
S
Owen
K
K
Hughes
P J
PJ
Waring
R H
RH
Kirk
C J
CJ
D015239:Arylsulfotransferase; D001792:Blood Platelets / Q000201:enzymology; D001943:Breast Neoplasms / Q000209:etiology / Q000628:therapy; D002460:Cell Line; D002553:Cerebroside-Sulfatase / Q000037:antagonists & inhibitors; D004967:Estrogens / Q000378:metabolism*; D005419:Flavonoids / Q000378:metabolism; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D048789:Phytoestrogens; D028321:Plant Preparations / Q000494:pharmacology*; D020033:Protein Isoforms / Q000378:metabolism; D012307:Risk Factors; D043266:Steryl-Sulfatase / Q000378:metabolism; D013379:Substrate Specificity; D013429:Sulfatases / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism*; D015238:Sulfotransferases / Q000378:metabolism
D004967:Estrogens; D005419:Flavonoids; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D020033:Protein Isoforms; D013431:Sulfates; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C020122:estrone sulfotransferase; D013429:Sulfatases; D043266:Steryl-Sulfatase; D002553:Cerebroside-Sulfatase