Ethinylestradiol interacts with liver microsomes and induces binding sites for steroid hormones in the male rat liver

Abstract

The present work focuses on the interaction of 17 alpha-ethinyl estrogen derivatives with the [H-3]dexamethasone ([H-3]DEX) binding site from male rat liver microsomes and the induction of this site by the in vivo administration of natural and synthetic estrogens. [H-3]DEX binds to a single-saturating binding site (K-d = 100 nM; maximal binding = 13 pmol/mg of protein) in the liver microsomes. In competition experiments, ethinylestradiol (EE(2)) and mestranol were able to inhibit [H-3]DEX binding to microsomes, whereas natural estrogens, tamoxifen or estrogen sulfates were ineffective. Saturation analysis performed by incubating [H-3]EE(2) With liver microsomes revealed the existence of a low-affinity (K-d = 230 +/- 30 nM) and high capacity (maximal binding = 16 +/- 2 pmol/mg of protein) binding site. Saturation, competition and dissociation experiments suggest that [H-3]DEX and [H-3]EE(2) interact with the same microsomal entity. Synthetic and natural estrogens increased the hepatic expression of the [H-3]DEX binding site in immature, hypothyroid and hypophysectomized male rats. This induction required at least 2 days of treatment, and could only be achieved by pharmacological doses of estrogens. These observations suggest that: 1) unlike natural estrogens, EE(2) and mestranol interact with the microsomal [H-3] DEX binding site; 2) [H-3]EE(2) and [H-3]DEX interact with a single entity in hepatic microsomes, which is different from both estrogen receptor and glucocorticoid receptor; 3) estrogens increase the level of the [H-3]DEX binding site, even in the absence of either pituitary hormones or hormones under pituitary control, thus suggesting a direct effect of estrogens on the hepatic synthesis of this binding site; and 4) EE(2) is the first molecule tested capable of both binding to and enhancing the expression of the [H-3]DEX binding site.