Structure activity relationships and differential interactions and functional activity of various equine estrogens mediated via estrogen receptors (ERs) ERalpha and ERbeta.
The human estrogen receptors (ERs) alpha and beta interact with 17beta-estradiol (17beta-E2), estrone, 17alpha-estradiol, and the ring B unsaturated estrogens, equilin, 17beta-dihydroequilin, 17alpha-dihydroequilin, equilenin, 17beta-dihydroequilenin, 17alpha-dihydroequilenin, Delta8-estrone, and Delta8, 17beta-E2 with varying affinities. In comparison to 17beta-E2, the relative binding affinities of most ring B unsaturated estrogens were 2- to 8-fold lower for ERalpha and ERbeta, however, some of these unique estrogens had two to four times greater affinity for ERbeta than ERalpha. The transcriptional activity of these estrogens in HepG2 cells transfected with ERalpha or ERbeta, or both, and the secreted-alkaline phosphatase gene showed that all estrogens were functionally active. 17beta-E2 induced the activity of secreted-alkaline phosphatase by ERalpha to a level higher than any other estrogen. Activity of other estrogens was 12-17% that of 17beta-E2. In contrast, 17beta-E2 stimulated the activity of ERbeta to a 5-fold lower level than that with ERalpha, whereas the activity of other estrogens was 66-290% that of 17beta-E2, with equilenin being the most active. The presence of both ER subtypes did not alter the functional activity of 17beta-E2, although it further enhanced the activity of 17beta-dihydroequilin (200%), 17beta-dihydroequilenin (160%), and Delta8, 17beta-E2 (130%). Except for 17beta-E2, no correlation was observed between the functional activities and their binding affinities for ER. In conclusion, our results show that the effects of ring B unsaturated estrogens are mainly mediated via ERbeta and that the presence of both ER subtypes further enhances their activity. It is now possible to develop hormone replacement therapy using selective ring B unsaturated estrogens for target tissues where ERbeta is the predominant ER.
Bhavnani
Bhagu R
BR
Department of Obstetrics and Gynecology, Institute of Medical Sciences, University of Toronto, and The Keenan Research Center of Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. bhavnani@smh.toronto.on.ca
Tam
Shui-Pang
SP
Lu
Xiaofeng
X
D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D004958:Estradiol / Q000737:chemistry / Q000493:pharmacokinetics; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004966:Estrogens, Conjugated (USP) / Q000737:chemistry* / Q000493:pharmacokinetics*; D017930:Genes, Reporter; D006801:Humans; D008113:Liver Neoplasms; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014162:Transfection; D014316:Tritium
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004966:Estrogens, Conjugated (USP); D014316:Tritium; D004958:Estradiol