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The Stehlin Foundation for Cancer Research, 1918 Chenevert St, Houston, TX 77003, USA

(Requests for offprints should be addressed to C S A Markides; Email: cmarkides{at}stehlin.org)

There are several indications of a possible physiological role for 4-hydroxyestradiol (4-OHE₂) in hormone-responsive tissues. To examine a hormonal activity of 4-OHE₂, we have studied the binding of ³H-labeled 4-OHE₂ to mouse uterine cytosolic protein. In uteri of 3-week-old mice, total binding was 319.4 ± 13.9 fmol/mg protein. Binding in the presence of excess unlabeled 4-OHE₂ dropped to 82.1 ± 1.7 fmol/mg protein, whereas 214.6 ± 9.4 fmol/mg protein bound while incubating in an excess of unlabeled 17ß-estradiol (E₂). The difference between the two binding values in the presence of excess steroid (132.5 ± 11.1 fmol/mg protein) is taken as selective binding of 4-OHE₂ to a specific protein. In mice older than 4 weeks, the specific 4-OHE₂ binding declined: 32.0 ± 4.0 fmol/mg protein at 8 weeks, 54.8 ± 6.3 fmol/mg protein at 12 weeks and 54.6 ± 5.2 fmol/mg protein at 9 months. Of other organs tested (liver, kidney, lung and whole brain) only lung showed significant selective binding of 4-OHE₂. When E₂-binding sites are blocked, binding follows first-order kinetics, yielding a dissociation constant (K_d) value of 11.8 ± 2.1 nM. The specific binding of 4-OHE₂ was not inhibited by any other steroids or estrogen metabolites that were tested, except for 2-hydroxyestradiol (2-OHE₂), which displayed competitive inhibition of 4-OHE₂ binding with an inhibition constant (K_i) value of 98.2 ± 12.6 nM. These results lead us to conclude that 4-OHE₂ binds to a specific binding protein, distinct and different from binding to estrogen receptors (ER and ERß). The physiological role of this binding remains to be elucidated.