Urolithins A
and B (hydroxy-6
H-dibenzo[
b,d]pyran-6-one derivatives) are colonic microflora metabolitesrecently proposed as biomarkers of human exposure to dietary ellagic acid derivatives. Molecularmodels suggest that urolithins could display estrogenic
and/or antiestrogenic activity. To this purpose,both urolithins
and other known phytoestrogens (genistein, daidzein, resveratrol,
and enterolactone)were assayed to evaluate the capacity to induce cell proliferation on the estrogen-sensitive humanbreast cancer MCF-7 cells as well as the ability to bind to
![](/images/gifchars/alpha.gif)
-
and ![](/images/gifchars/beta2.gif)
-estrogen receptors. Both urolithinsA
and B showed estrogenic activity in a dose-dependent manner even at high concentrations (40
![](/images/entities/mgr.gif)
M), without antiproliferative or toxic effects, whereas the other phytoestrogens inhibited cellproliferation at high concentrations. Overall, urolithins showed weaker estrogenic activity than theother phytoestrogens. However, both urolithins displayed slightly higher antiestrogenic activity(antagonized the growth promotion effect of 17-
![](/images/gifchars/beta2.gif)
-estradiol in a dose-dependent manner) than theother phytoestrogens. The IC
50 values for the ER
and ER
![](/images/gifchars/beta2.gif)
binding assays were 0.4
and 0.75
![](/images/entities/mgr.gif)
Mfor urolithin A; 20
and 11
![](/images/entities/mgr.gif)
M for urolithin B; 3
and 0.02 for genistein;
and 2.3
and 1 for daidzein,respectively; no binding was detected for resveratrol
and enterolactone. Urolithins A
and B enteredinto MCF-7 cells
and were metabolized to yield mainly urolithin-sulfate derivatives. These results,together with previous studies regarding absorption
and metabolism of dietary ellagitannins
and ellagicacid in humans, suggest that the gut microflora metabolites urolithins are potential endocrine-disruptingmolecules, which could resemble other described "enterophytoestrogens" (microflora-derivedmetabolites with estrogenic/antiestrogenic activity). Further research is warranted to evaluate thepossible role of ellagitannins
and ellagic acid as dietary "pro-phytoestrogens".Keywords: Breast cancer; phytoestrogen; hydroxy-6
H-dibenzo[
b,d]pyran-6-one derivative; endocrine-disrupting; estrogen receptor