THE ESTROGENIC AND ANTIESTROGENIC ACTIVITIES OF PHYTOCHEMICALS WITH HUMAN ESTROGEN-RECEPTOR EXPRESSED IN YEAST

We have used the expression of the human estrogen receptor (hER) and t wo estrogen response elements linked to the lacZ gene in yeast (YES) t o study the estrogenic and antiestrogenic activities of various phytoc hemicals. Coumestrol, alpha-zearalenol, or genistein could produce bet a-galactosidase activity comparable to estradiol, but these required c oncentrations 100 to 1000-fold greater than estradiol. These compounds did not possess antiestrogenic activity. Narigenin, kaempferide, phlo retin, biochanin A, flavone, or chrysin only partially induced beta-ga lactosidase activity in the YES at any concentration tested. When nari genin, kaempferide, or phloretin was given concurrently with estradiol , the estradiol-dependent beta-galactosidase activity was not inhibite d by more than 50%. However, biochanin A, flavone, or chrysin could in hibit the activity of estradiol in a dose-response manner with IC50 va lues of 500 nM, 2 mu M, and 10 mu M, respectively. Combinations of bio chanin A, chrysin, and flavone decreased estradiol-dependent beta-gala ctosidase activity in an additive fashion. Similar to the antiestrogen s tamoxifen or ICI 182, 780, the antiestrogenic activity of these comp ounds with the exception of chrysin involved the disruption of hER dim erization, as demonstrated in the yeast two-hybrid system. Biochanin A , chrysin, or flavone were less effective in inhibiting the activity o f an estrogenic polychlorinated biphenyl than they were inhibiting the activity of estradiol. Interestingly, this latter group of antiestrog enic phytocompounds did not inhibit the estrogenic activity of such ph ytochemicals as coumestrol or genistein. These results suggest that th e antiestrogenic activity of biochanin A and flavone occurs by a mecha nism similar to tamoxifen or ICI 182, 780. Moreover, it seems that phy tochemicals functioning as antiestrogens do not inhibit the activity o f all estrogenic chemicals to the same extent. This suggests that conf ormational changes induced by different estrogens bound to the hER may regulate the antiestrogenic activity of a compound. (C) 1997 by Elsev ier Science Inc.