Effect of genistein on native epithelial tissue from normal individuals and CF patients and on ion channels expressed in Xenopus oocytes
- 1 August 2000
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 130 (8), 1884-1892
- https://doi.org/10.1038/sj.bjp.0703520
Abstract
The flavonoid genistein has been shown to activate a Cl(-) conductance in various cell types expressing CFTR. We examined if similar effects can be observed when genistein is applied to native ex vivo tissues from human respiratory tract and rectum. We further compared the effects when genistein was applied to oocytes of Xenopus laevis expressing CFTR. In oocytes, both wtCFTR and DeltaF508-CFTR were activated by genistein while both cyclic AMP (K(v)LQT1) and Ca(2+) (SK4) activated K(+) channels were inhibited at high concentrations of genistein. Biopsies from nasal polyps and rectal mucosa were obtained from normal individuals (non-CF) and CF patients and in the presence of amiloride (10 micromol l(-1); mucosal side) the effects of genistein were assessed using a perfused Ussing chamber. In non-CF airway epithelia, genistein (50 micromol l(-1); mucosal side) increased lumen negative I(sc) but had no additional effects on tissues pre-stimulated with IBMX and forskolin (100 micromol l(-1) and 1 micromol l(-1); both sides). In non-CF rectal biopsies, in the presence of amiloride (10 micromol l(-1); mucosal side) and indomethacin (10 micromol l(-1); basolateral side), genistein increased lumen negative I(sc) and enabled cholinergic (carbachol; CCH, 100 micromol l(-1); basolateral side) stimulation of Cl(-) secretion indicating activation of luminal CFTR Cl(-) channels. However, after stimulation with IBMX/forskolin, genistein induced opposite effects and significantly inhibited CCH activated I(sc). In CF airway and intestinal tissues genistein failed to induce Cl(-) secretion. Thus, genistein is able to activate luminal CFTR Cl(-) conductance in non-CF tissues and mutant CFTR in oocytes. However, additional inhibitory effects on basolateral K(+) conductance and missing effects in native CF tissues do not support the use for pharmacological intervention in CF.Keywords
This publication has 42 references indexed in Scilit:
- The pharmacology of hSK1 Ca2+‐activated K+ channels expressed in mammalian cell linesBritish Journal of Pharmacology, 2000
- The amiloride-inhibitable Na+ conductance is reduced by the cystic fibrosis transmembrane conductance regulator in normal but not in cystic fibrosis airways.JCI Insight, 1998
- The diagnosis of cystic fibrosis: A consensus statementThe Journal of Pediatrics, 1998
- Coexpression of Ligand-gated P2X and G Protein-coupled P2Y Receptors in Smooth MusclePublished by Elsevier ,1998
- Direct action of genistein on CFTRPflügers Archiv - European Journal of Physiology, 1997
- Genistein Directly Induces Cardiac CFTR Chloride Current by a Tyrosine Kinase-Independent and Protein Kinase A-Independent Pathway in Guinea Pig Ventricular MyocytesBiochemical and Biophysical Research Communications, 1997
- Modulation of Cl− secretion in rat distal colon by genistein, a protein tyrosine kinase inhibitorEuropean Journal of Pharmacology, 1996
- Mutations in the putative pore‐forming domain of CFTR do not change anion selectivity of the cAMP activated Cl− conductanceFEBS Letters, 1995
- Failure of cholinergic stimulation to induce a secretory response from the rectal mucosa in cystic fibrosis.Gut, 1991
- FORSKOLIN INCREASES cAMP AND INHIBITS PROGESTERONE INDUCED MEIOSIS REINITIATION IN XENOPUS LAEVIS OOCYTESEndocrinology, 1982