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Vol. 295, Issue 1, 195-204, October 2000

Estrogen Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Chloride Secretion1

Ashvani K. Singh, Bruce D. Schultz, John A. Katzenellenbogen, Elmer M. Price, Robert J. Bridges and Neil A. Bradbury

Cystic Fibrosis Research Center, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (A.K.S., R.J.B., N.A.B.); Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas (B.D.S.); Department of Chemistry, University of Illinois at Urbana-Champaign, Illinois (J.A.K.); and Dalton Cardiovascular Research Institute, University of Missouri, Missouri (E.M.P.)

Cystic fibrosis (CF) is an autosomal genetic disease associated with impaired epithelial ion transport. Mutations in the CF gene alter the primary sequence of the CF transmembrane conductance regulator (CFTR). Several therapeutic modalities have been proposed for CF patients, including the phytoestrogen genistein. Experiments were completed in cellular and subcellular systems to evaluate the impact of naturally occurring and synthetic estrogens on epithelial ion transport, and specifically on the CF protein CFTR. 17beta -Estradiol, a naturally occurring estrogen, caused a rapid and reversible inhibition of forskolin-stimulated chloride secretion across T84 epithelial cell monolayers with a Ki of 8 µM. In addition, 17alpha -estradiol, a stereoisomer that fails to bind and activate nuclear estrogen receptors was equipotent with 17beta -estradiol, arguing against a genomic-mediated mechanism of action. Synthetic estrogens, including diethylstilbesterol and the antiestrogen tamoxifen likewise inhibited forskolin-stimulated ion transport. Aldosterone, dexamethasone, and cholesterol were without effect at the highest concentrations tested (>= 1 mM). Studies indicated that diethylstilbesterol and other synthetic estrogens that inhibited anion secretion in intact monolayers likewise inhibited CFTR chloride channel activity with similar concentration dependencies in excised membrane patches. Experiments with radioactive photoactivatable estrogen derivatives demonstrated that these compounds bind directly to CFTR expressed in insect cells. Taken together, the data suggest that estrogens can interact directly with CFTR to alter anion transport.

1 This study was supported in part by the Cystic Fibrosis Foundation Grants 1974 (to A.K.S.) and SCHUL960 (to B.D.S.), and National Institutes of Health Grants DK47850 (to N.A.B.) and DK15556 (to J.A.K.).

0022-3565/00/2951-0195$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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