Influence of estrogen structure on nuclear binding and progesterone receptor induction by the receptor complex

Abstract

The relationship between steroid structure, estrogen receptor (ER) binding affinity, nuclear binding of the ER complex, and induction of progesterone receptor (PgR) have been examined. The level of ER in membrane-free homogenates of MCF-7 cells was found to be 10.0 +/- 0.5 fmol/micrograms of DNA by utilizing an enzyme immunoassay (EIA). However, only 2.5 +/- 0.2 fmol of ER complex/micrograms of DNA was bound by nuclei during maximal stimulation of PgR synthesis (2.9 +/- 0.2 fmol of PgR/micrograms of DNA; measured by EIA) following a pulse with 10(-10) M E2. Except at micromolar concentrations, estratriene was an ineffective estrogen. The addition of a hydroxyl group to either position 3 or position 17 beta of estratriene yielded ligands which were capable of causing nuclear binding and processing of ER as well as PgR induction. D-ring regioisomers of estradiol (E2) had lower affinity for receptor than E2. However, receptor complexed with these estrogens was fully capable of binding to nuclear material, undergoing processing, and inducing PgR. On the other hand, A-ring regioisomers of E2 displayed significant differences in their ability to mediate nuclear binding of receptor complex and induction of PgR. Although 1-hydroxyestratrien-17 beta-ol was weakly bound by ER, this dihydroxyestrogen was capable of bringing about nuclear binding and processing of ER and the stimulation of PgR synthesis. In contrast, 2- and 4-hydroxyestratrien-17 beta-ol, which caused extensive nuclear binding of ER (5-7 fmol/micrograms of DNA), were incapable of significant PgR induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicity of Endogenous and Environmental Estrogens: What Is the Role of Elemental Interactions?

“…They examined the ability of a series of estradiol analogs to bind to the estrogen receptor and elicit biological responses including induction of the progesterone receptor, pS2 mRNA, cathepsin D mRNA, and CAT activity from reporter constructs containing the c-ERE. They found clearly different patterns of activation of these responses by the different estrogen analogs (45)(46)(47) and emphasized the possible biological significance of these observations.…”

“…Perhaps the clearest example of this possiblity to date comes from a recent series of experiments from Brooks and his colleagues (45)(46)(47). They examined the ability of a series of estradiol analogs to bind to the estrogen receptor and elicit biological responses including induction of the progesterone receptor, pS2 mRNA, cathepsin D mRNA, and CAT activity from reporter constructs containing the c-ERE.…”

Quantitative structure‐activity relationships for polychlorinated hydroxybiphenyl estrogen receptor binding affinity: An Assessment of conformer flexibility

“…Thus, it appears that ER binding energy is sufficiently large to offset the energy needed for conversion of conformers to a preferred geometry [6]. In a related series of studies on the structural requirements for ER binding and associated estrogenic responses, it was inferred that hydroxylation at specific sites of the estratrien-17␤-ol aromatic A ring is critical [10,11]. Hydroxylation at the 2 or 3 (i.e., E 2 ) positions promoted high affinity of a ligand for the ER, while hydroxylation at the 1 or 4 positions attenuated binding affinity (see Fig.…”

“…1 for the location of these positions in E 2 ). It has been hypothesized that the hydroxyl groups at positions 2 and 3 may share, via hydrogen bonding, a common H acceptor/donor site in the receptor cavity [10].…”

“…The results of these studies showed that considerations of the degree of conformational planarity are critical to the generation of robust structure-affinity models for binding. As discussed previously, the role of ligand conformational flexibility in elucidating the relationship between electronic character, ER binding, and estrogenic responses is also of great interest [4][5][6]10,11]. To further study the role of PCB conformer flexibility on biological activity, a multipleconformer QSAR method was employed to model ER binding affinity of E 2 , diethylstilbestrol (DES), and the series of PCHBs investigated by Korach et al [14] and Waller et al [3].…”