RT Journal Article
SR Electronic
T1 Estrogen Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Chloride Secretion
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 195
OP 204
VO 295
IS 1
A1 Ashvani K. Singh
A1 Bruce D. Schultz
A1 John A. Katzenellenbogen
A1 Elmer M. Price
A1 Robert J. Bridges
A1 Neil A. Bradbury
YR 2000
UL http://jpet.aspetjournals.org/content/295/1/195.abstract
AB 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. 17β-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, 17α-estradiol, a stereoisomer that fails to bind and activate nuclear estrogen receptors was equipotent with 17β-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. The American Society for Pharmacology and Experimental Therapeutics