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

Abstract

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.

A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone

“…Presumably, 7,8-dihydroxyflavone might not inhibit aromatase, either. In addition to the activity described above, 7,8-dihydroxyflavone also has been shown to inhibit aldehyde dehydrogenase and estrogen sulfotransferase in vitro with K i values of 35 μM and 1-3 μM, respectively (23,24). However, these actions have not been confirmed in animals.…”

Improving the oral bioavailability of beneficial polyphenols through designed synergies

“…There are a number of reports indicating that various flavonoids, such as hexamethoxyflavone, tangeretin and silybin are potent inhibitors of UGTs in vitro, with IC 50 values \1 lM [72,83,84]. Similarly, a number of flavonoids (fisetin, galangin, quercetin, myricetin, chrysin, kaempferol, apigenin and genistein) have been identified in vitro as potent inhibitors of various SULTs [15,26,52], but as with the UGTs, it is not known whether such in vitro interactions translate into significant in vivo effects.…”

Phytoestrogens and their Potential Role in Prostate Cancer Prevention and Treatment

“…Nishiyama et al [44] reported that daidzein and genistein are predominantly sulfated by SULT1A1 and SULT1E1, respectively in humans and inhibit the sulfation of the endogenous substrate, beta-estradiol. Harris et al [41] demonstrated that equol, genistein and daidzein inhibited human SULT1E1 in that order of potency. Human SULT1A1, another sulfotransferase involved in the sulfation of estrogens, also uses daidzein as a substrate, and is inhibited by both daidzein and genistein at similar concentrations [38].…”

“…Genistein and daidzein can inhibit and induce various enzymes involved in sex steroid metabolism [37][38][39][40][41][42]. They inhibit steroid metabolizing enzymes such as 5-alpha reductase [29], aromatase [7,39] and 17-β hydroxysteroid dehydrogenase Type 1 [37].…”