R‐Equol‐induced non‐genomic estrogenic effects and interactions with estradiol signaling

Abstract

We previously reported that phytoestrogens, including daidzein, are potent inducers of nongenomic responses acting via membrane receptors for estrogens (mERs). R‐Equol (R‐Eq), a metabolite of daidzein, preferentially binds mERα. Therefore, we examined R‐Eq‐ induced nongenomic effects in mERα‐enriched GH3/B6/F10 pituitary tumor cells at the cellular signaling and function levels. R‐Eq (15 nM, dietary level), compared to 1 nM estradiol (E2, a female physiologic level), induced mitogen‐activated protein kinase (MAPK) activities (pERK, pJNK and p38) with variant initial peaks in the 2.5–15 min range and subsequent oscillations, as we have observed for other estrogens previously. In contrast to E2, R‐Eq did not produce a dose‐dependent increase in cell proliferation. R‐equol, like E2, augmented intracellular Ca++ levels and prolactin release from pituitary tumor cells. R‐Eq and E2 both alone and combined significantly activated Gαi by GTP‐charging. R‐Eq (10−16 to 10−7M) combined with 1 nM E2 significantly suppressed pERK, pJNK and p38 activities and cell proliferation, especially at concentrations of 10−10to 10−7M. We conclude that R‐Eq, like E2, is a rapid activator of nongenomic signals, but with slight differences in timing patterns and efficacies. However, when R‐Eq is combined with E2, it sometimes interferes with E2‐induced nongenomic estrogenic effects.