Mechanism of the estrogen receptor interaction with 4-hydroxytamoxifen.
The binding mechanism of the estrogen receptor with 4-[3H]hydroxytamoxifen was investigated. The equilibrium binding analysis with 4-[3H]hydroxytamoxifen indicated a positive cooperative interaction: the Scatchard plot was convex and the Hill coefficient was 1.4-1.5. This binding appears similar to the positively cooperative interaction of the estrogen receptor with [3H]estradiol. However, a competitive binding assay with a saturating concentration of [3H] estradiol and variable concentrations of 4-hydroxytamoxifen produced nonparallel displacement curves indicating that the binding mechanism of the receptor with these two ligands is different. The competitive binding assay with [3H]estradiol and 4-hydroxytamoxifen at constant molar ratios demonstrated that the receptor's affinity for estradiol was reduced and the receptor preferentially bound 4-hydroxytamoxifen. These data suggest that 4-hydroxytamoxifen interacts with the receptor differently than estradiol; it antagonizes the binding of estradiol when these two ligands are simultaneously present.
Sasson
S
S
Department of Pharmacology, Hebrew University School of Medicine, Jerusalem, Israel.
Notides
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D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D004958:Estradiol / Q000378:metabolism; D004964:Estriol / Q000378:metabolism; D005260:Female; D007700:Kinetics; D011487:Protein Conformation / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
D011960:Receptors, Estrogen; D013629:Tamoxifen; D014316:Tritium; C016601:afimoxifene; D004958:Estradiol; D004964:Estriol