17 Alpha-ethinyl estradiol is more potent than estradiol in receptor interactions with isolated hepatic parenchymal cells.

Estradiol (E2) and 17 alpha-ethinyl estradiol (EE2) were compared for their abilities to promote nuclear translocation of the hepatic estrogen receptor. High levels of nonradioactive E2 and EE2 were incubated in vitro with isolated rat liver parenchymal cells. Cytosol and nuclear receptors were then partially purified and measured by exchange with [3H]E2. E2 was required in an approximately 100-fold higher concentration than EE2 for promotion of receptor translocation (for example, 10(-5) M E2 was equivalent to 10(-7) M EE2). When the metabolisms of the estrogens by parenchymal cells were compared, it was found that [3H]E2 was metabolized much more extensively than [3H]EE2 after a short time interval. Inhibitors of estrogen metabolism were used to test the hypothesis that the high dose requirement for receptor translocation may be due to metabolism. In isolated liver cells, SKF 525A (beta-diethylaminoethyl-2,2-diphenylpentanoate; an inhibitor of hepatic mixed function oxidase) could increase levels of unmetabolized EE2, cytosol receptor deletion, and nuclear receptor accumulation. SKF 525A alone was not sufficient to increase levels of unmetabolized E2 or receptor translocation in the presence of this estrogen. When testosterone (a transient inhibitor of the 17-oxidoreductase active on E2) was included in cellular incubations (using female liver cells) with E2 and SKF 525A, levels of unmetabolized E2 were substantially increased in conjunction with increased depletion of cytosol receptors and increased levels of nuclear receptors. These data suggest that hepatic metabolism may limit the availability of estrogens for binding to receptors. The present study suggests that E2 is more extensively metabolized than EE2 to metabolites which are less capable of promotion of receptor translocation.