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Departments of Physiology and Biophysics, and Chemistry, University of Illinois, and School of Basic Medical Sciences, University of Illinois College of Medicine Urbana, Illinois 61801
Address all correspondence and requests for reprints to: Dr. B. S. Katzenellenbogen, Department of Physiology and Biophysics, 524 Burrill Hall, University of Illinois, Urbana, Illinois 61801.
Abstract
This study investigates the direct estrogen receptor interactions and the character of the biological activities of three estrogenic resorcylic acid lactones in the immature rat uterus. These compounds are fungal metabolites (P-1492; zearalenone) or derivatives thereof (P-1496 and P-1560; epimeric zearalanols) that have been associated with estrogenizing syndromes in cattle fed mold-infected grain. The compounds compete with estradiol for binding to the cytoplasmic receptor (P- 1496, 13.6%; P-1492, 1.8%; P-1560, 0.8% that of estradiol), and they translocate estrogen receptor sites to the nucleus, with P- 1496 showing the most prolonged nuclear receptor interaction. The three compounds induce the synthesis of the uterine induced protein (P-1496 > P-1560 > P-1492) and increase uterine weight. Direct binding studies with the most potent compound P-1496, in tritium-labeled form indicates a Kd of 1.8 nM (compared to 0.12 nM for estradiol) for interaction with uterine cytoplasmic receptor. Cytoplasmic receptor complexes with [3H]P-1496 sediment at 8S on low salt sucrose density gradients, as do [&HJestradiol receptor complexes. After uterine uptake of [3H]P-1496, salt-extracted nuclear receptor complexes sediment at 5.4S on 0.4 M KC1 sucrose density gradients, as do the nuclear [3H]estradiol receptor complexes. These studies document that despite the unique chemical nature of these resorcylic acid lactones, they interact directly with the estrogen receptor and evoke many of the same biological and biochemical responses that are evoked by the natural estrogen estradiol.
Footnotes
* This work was supported by NIH Grants USPH HD-06726 and CA-18119 (B.S.K.) and AM-15556 (J.A.K.) and American Cancer Society Grant BC-223 (J.A.K.).
Present address: Stanford University School of Medicine, Stanford, California.
Received December 11, 1978.
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