17-Epiestriol, an Estrogen Metabolite, Is More Potent Than Estradiol in Inhibiting Vascular Cell Adhesion Molecule 1 (VCAM-1) mRNA Expression

Abstract

17-␤ estradiol (17-␤ E 2 ) attenuates the expression of vascular cell adhesion molecule 1 (VCAM-1) in vivo at physiological levels (pg/ml), whereas supraphysiological concentrations of 17-␤ E 2 (ng/ml) are required in vitro. We assessed whether a metabolite of estrogen, which could only be generated in vivo, might be a more potent inhibitor of VCAM-1 expression and thereby explain this discrepancy. We report here that 17-epiestriol, an estrogen metabolite and a selective estrogen receptor (ER) ␤ agonist, is ϳ400؋ more potent than 17-␤ E 2 in suppressing tumor necrosis factor (TNF) ␣-induced VCAM-1 mRNA as well as protein expression in human umbilical vein endothelial cells. Genistein, an ER␤ agonist, at low concentrations (1 and 10 nM) also suppressed TNF␣-induced VCAM-1 mRNA expression. These actions of 17-epiestriol and genistein were significantly attenuated in the presence of the estrogen receptor antagonist ICI-182780. Other estrogenic compounds such as ethinyl estradiol and estrone did not have any effect on TNF␣-induced VCAM-1 expression at the concentrations tested. We further show that, 1) 17-epiestriol induces the expression of endothelial nitric-oxide synthase mRNA and protein, 2) 17-epiestriol prevents TNF␣-induced migration of NFB into the nucleus, 3) N G -nitro-L-arginine methyl ester, an inhibitor of NO synthesis, abolishes 17-epiestriol-mediated inhibition of TNF␣-induced VCAM-1 expression and migration of NFB from the cytoplasm to the nucleus. Our results indicate that 17-epiestriol is more potent than 17-␤ E 2 in suppressing TNF␣-induced VCAM-1 expression and that this action is modulated at least in part through NO.The mechanism by which estrogens attenuate the development of atherosclerosis is not known, although various actions of estrogens have been suggested to mediate this effect (1). We have previously demonstrated that 17-␤ estradiol (17-␤ E 2 ) in vivo inhibits the adhesion of monocytes to endothelial cells of the rabbit aorta (2). We also demonstrated that following a cholesterol-enriched diet to ovariectomized rabbits, expression of VCAM-1 1 protein was induced in the aorta, and this was attenuated by administration of 17-␤ E 2 (2). Treatment of cultured rabbit aortic endothelial cells with 17-␤ E 2 also attenuated the lysophosphatidylcholine-induced expression of VCAM-1 protein. However, the concentrations of 17-␤ E 2 required to suppress VCAM-1 expression in vitro were in the supraphysiological range when compared with the physiological levels required for in vivo studies. We therefore postulated that one mechanism by which only relatively low concentrations of 17-␤ E 2 were required for in vivo studies when compared with in vitro studies was that 17-␤ E 2 might be converted to a more potent metabolite in vivo (2).Some effects of estrogens are mediated through non-genomic mechanisms, whereas others require transcriptional activation of genes (3). These latter actions usually require that estrogens combine with specific receptors. Two types of estrogen receptors (ER) have been descr...

Regiospecificity and Stereospecificity of Human UDP-Glucuronosyltransferases in the Glucuronidation of Estriol, 16-Epiestriol, 17-Epiestriol, and 13-Epiestradiol

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