Two principle soy-derived isoflavones, genistein and daidzein, are believed to play a key role in inhibiting tumor growth. The molecular basis of the anti-tumor activity of these two isoflavones has not been fully established. To determine the mechanism of action of the above phytochemicals on estrogen-responsive genes, we tested the effect of the same on the expression of Estrogen-Regulated mRNA Stabilizing Factor (E-RmRNASF). E-RmRNASF is expressed in the liver in response to estrogen, and is responsible for estrogen-mediated stabilization of apolipoprotein II mRNA (Ratnasabapathy, 1995, Cell. Mol. Biol. Res, 41: 583-594). The estrogen-mediated hepatic expression of apolipoprotein II mRNA is regulated transcriptionally, and also post-transcriptionally in part by stabilization of its mRNA. E-RmRNASF protects the RNA from targeted endonucleolytic degradation. The hepatic expression of E-RmRNASF is also modulated by certain estrogenic and antiestrogenic nonsteroidal environmental xenobiotics (Ratnasabapathy et al., 1997, Biochem. Pharmacol., 53: 1425-1434). Roosters were administered estrogen, genistein, or daidzein parenterally and tested for hepatic expression of E-RmRNASF. Expression of E-RmRNASF in the livers was stimulated in roosters who received estrogen and genistein, indicating that they are agonistic at the chicken estrogen receptor. However, a lack of induction of E-RmRNASF expression in the liver was seen with control roosters treated with the vehicle and those treated with daidzein. To determine whether daidzein was. anti-estrogenic, roosters were given combinations of estrogen and increasing concentrations of daidzein. Daidzein at concentrations ranging from 5-1000 mumole/kg failed to antagonize stimulation of E-RmRNASF by 5 mumoles/kg estrogen. To determine whether genistein or daidzein exerted partial agonistic effects, roosters were given increasing concentrations of genistein, daidzein or estrogen alone, or combinations of estrogen and increasing doses of genistein or daidzein. At low to intermediate concentrations genistein by itself failed to stimulate E-RmRNASF, and was agonistic only at high concentrations. Genistein at the low concentrations failed to antagonize estrogenic stimulation of E-RmRNASF. At the intermediate concentrations however, genistein blocked stimulation of E-RmRNASF by estrogen, even though by itself could not exert a stimulatory effect. At the higher concentrations genistein stimulated E-RmRNASF regardless of the presence or absence of estrogen. At the higher ratios, the lack of inhibition of estrogenic stimulation by genistein was most likely due to its own agonistic activity. Therefore, genistein appears to behave as a partial agonist; behaves as an agonist by itself, and as an antagonist in the presence of estrogen. However, daidzein did not display any estrogenic or antiestrogenic activity at the concentrations tested. (C) 2002 Elsevier Science Inc. All rights reserved.
