The estrogenic and antiestrogenic activities of phytochemicals with the human estrogen receptor expressed in yeast.

We have used the expression of the human estrogen receptor (hER) and two estrogen response elements linked to the lacZ gene in yeast (YES) to study the estrogenic and antiestrogenic activities of various phytochemicals. Coumestrol, alpha-zearalenol, or genistein could produce beta-galactosidase activity comparable to estradiol, but these required concentrations 100 to 1000-fold greater than estradiol. These compounds did not possess antiestrogenic activity. Narigenin, kaempferide, phloretin, biochanin A, flavone, or chrysin only partially induced beta-galactosidase activity in the YES at any concentration tested. When narigenin, kaempferide, or phloretin was given concurrently with estradiol, the estradiol-dependent beta-galactosidase activity was not inhibited by more than 50%. However, biochanin A, flavone, or chrysin could inhibit the activity of estradiol in a dose-response manner with IC50 values of 500 nM, 2 microM, and 10 microM, respectively. Combinations of biochanin A, chrysin, and flavone decreased estradiol-dependent beta-galactosidase activity in an additive fashion. Similar to the antiestrogens tamoxifen or ICI 182, 780, the antiestrogenic activity of these compounds with the exception of chrystin involved the disruption of hER dimerization, as demonstrated in the yeast two-hybrid system. Biochanin A, chrysin, or flavone were less effective in inhibiting the activity of an estrogenic polychlorinated biphenyl than they were inhibiting the activity of estradiol. Interestingly, this latter group of antiestrogenic phytocompounds did not inhibit the estrogenic activity of such phytochemicals as coumestrol or genistein. These results suggest that the antiestrogenic activity of biochanin A and flavone occurs by a mechanism similar to tamoxifen or ICI 182,780. Moreover, it seems that phytochemicals functioning as antiestrogens do not inhibit the activity of all estrogenic chemicals to the same extent. This suggests that conformational changes induced by different estrogens bound to the hER may regulate the antiestrogenic activity of a compound.