Quantitative Structure-Activity Relationship of Various Endogenous Estrogen Metabolites for Human Estrogen Receptor α and β Subtypes: Insights into the Structural Determinants Favoring a Differential Subtype Binding

Abstract

To search for endogenous estrogens that may have preferential binding affinity for human estrogen receptor (ER) alpha or beta subtype and also to gain insights into the structural determinants favoring differential subtype binding, we studied the binding affinities of 74 natural or synthetic estrogens, including more than 50 steroidal analogs of estradiol-17beta (E2) and estrone (E1) for human ER alpha and ER beta. Many of the endogenous estrogen metabolites retained varying degrees of similar binding affinity for ER alpha and ER beta, but some of them retained differential binding affinity for the two subtypes. For instance, several of the D-ring metabolites, such as 16 alpha-hydroxyestradiol (estriol), 16 beta-hydroxyestradiol-17 alpha, and 16-ketoestrone, had distinct preferential binding affinity for human ER beta over ER alpha (difference up to 18-fold). Notably, although E2 has nearly the highest and equal binding affinity for ER alpha and ER beta, E1 and 2-hydroxyestrone (two quantitatively predominant endogenous estrogens in nonpregnant woman) have preferential binding affinity for ER alpha over ER beta, whereas 16 alpha-hydroxyestradiol (estriol) and other D-ring metabolites (quantitatively predominant endogenous estrogens formed during pregnancy) have preferential binding affinity for ER beta over ER alpha. Hence, facile metabolic conversion of parent hormone E2 to various metabolites under different physiological conditions may serve unique functions by providing differential activation of the ER alpha or ER beta signaling system. Lastly, our computational three-dimensional quantitative structure-activity relationship/comparative molecular field analysis of 47 steroidal estrogen analogs for human ER alpha and ER beta yielded useful information on the structural features that determine the preferential activation of the ER alpha and ER beta subtypes, which may aid in the rational design of selective ligands for each human ER subtype.

Dual roles of estrogen metabolism in mammary carcinogenesis

“…Membrane-bound form of ERα, ERβ, or both is suggested to be associated with nongenomic pathway which may provide the plat-form for the crosstalk with growth factor-mediated signaling transduction pathways (72,73). It is thought that either ER or growth factor-mediated signaling pathway is converged on activation of MAPK pathways that play a critical role in regulation of apoptosis, cell proliferation, and cell-cycle control, thereby, leading to growth of tissue and/or tumor (67,72) (23,77). It is of our special interest that O-methoxylated catechol estrogens also displayed the proliferative effects via genomic ER signaling pathways and enhanced tumor growth in animal models (26,27).…”

Estriol has different effects from 17β-estradiol in modulating mouse splenocyte function under inflammatory conditions

“…E 3 is usually produced only in a very small quantity in a non-pregnant woman, but it becomes a quantitatively-major estrogen during pregnancy (Fotsis, 1987). Interestingly, while E 2 has very high binding affinity for both human ERα and ERβ, the relative binding affinities of E 3 for human ERα and ERβ are 11% and 35%, respectively, of that of E 2 (Zhu et al, 2006), thus giving E 3 a 3.5-fold relative binding preference for ERβ over ERα. It has been speculated that E 3 may play a unique role in modulating the immune system function during pregnancy.…”

Az ösztrogénmetabolom biológiai és klinikai jelentősége lokális folyamatokban

“…Az egyes lebontási útvonalak metabolitjainak eltérő szerepük van a hormondependens betegsé-gek kialakulásában [27].…”