Article date: August 2000
By: Marcus Mall, Andreas Wissner, Hans H Seydewitz, Martin Hübner, Joachim Kuehr, Matthias Brandis, Rainer Greger, Karl Kunzelmann in Volume 130, Issue 8, pages 1884-1892
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 ΔF508‐CFTR were activated by genistein while both cyclic AMP (KvLQT1) and Ca2+ (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 μmol l−1; mucosal side) the effects of genistein were assessed using a perfused Ussing chamber. In non‐CF airway epithelia, genistein (50 μmol l−1; mucosal side) increased lumen negative Isc but had no additional effects on tissues pre‐stimulated with IBMX and forskolin (100 μmol l−1 and 1 μmol l−1; both sides).
In non‐CF rectal biopsies, in the presence of amiloride (10 μmol l−1; mucosal side) and indomethacin (10 μmol l−1; basolateral side), genistein increased lumen negative Isc and enabled cholinergic (carbachol; CCH, 100 μmol 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 Isc. 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.
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 ΔF508‐CFTR were activated by genistein while both cyclic AMP (KvLQT1) and Ca2+ (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 μmol l−1; mucosal side) the effects of genistein were assessed using a perfused Ussing chamber. In non‐CF airway epithelia, genistein (50 μmol l−1; mucosal side) increased lumen negative Isc but had no additional effects on tissues pre‐stimulated with IBMX and forskolin (100 μmol l−1 and 1 μmol l−1; both sides).
In non‐CF rectal biopsies, in the presence of amiloride (10 μmol l−1; mucosal side) and indomethacin (10 μmol l−1; basolateral side), genistein increased lumen negative Isc and enabled cholinergic (carbachol; CCH, 100 μmol 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 Isc. 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.
British Journal of Pharmacology (2000) 130, 1884–1892; doi:10.1038/sj.bjp.0703520
DOI: 10.1038/sj.bjp.0703520
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