Insights into the pharmacological potential of estrogens and phytoestrogens on catecholamine signaling

We report here the effects of estrogens and phytoestrogens on catecholamine signaling in cultured bovine adrenal medullary cells used as a model of catecholaminergic neurons in the brain. Treatment of the cells for 20 min with 17beta-estradiol (E(2)) (0.3-100 nM) or phytoestrogens such as daidzein (0.01-1.0 microM), a soy isoflavone, and resveratrol (0.1-1.0 microM), a grape polyphenol, stimulated (14)C-catecholamine synthesis from [(14)C]tyrosine, which was associated with the activation of tyrosine hydroxylase. The stimulatory effect of E(2) and phytoestrogens was not inhibited by ICI182,780, a nuclear estrogen receptor inhibitor, but abolished by U0126, an inhibitor of extracellular signal-regulated kinase1/2 (ERK1/2) kinase. E(2) enhanced the phosphorylation of ERK1/2. The plasma membrane isolated from the adrenal medulla showed two classes of specific binding sites of [(3)H]E(2). Resveratrol and daidzein at high concentrations (> or =1.0 microM) inhibited catecholamine secretion induced by various secretagogues. The present findings suggest that estrogens and phytoestrogens most likely stimulate catecholamine synthesis via estrogen receptors in the plasma membrane, but in high concentrations phytoestrogens inhibit catecholamine secretion induced by secretagogues in adrenal medullary cells, and probably in brain neurons.