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Br J Pharmacol. 2009 Nov;158(5):1313-21. doi: 10.1111/j.1476-5381.2009.00398.x. Epub 2009 Sep 25.

Differential activation of the HCO(3)(-) conductance through the cystic fibrosis transmembrane conductance regulator anion channel by genistein and forskolin in murine duodenum.

Author information

1
Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi, China. tuobiguang@yahoo.com.cn

Abstract

BACKGROUND AND PURPOSE:

Many cystic fibrosis (CF)-associated mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels affect CFTR-activated HCO(3)(-) transport more than Cl(-) transport. Targeting the CFTR HCO(3)(-) conductance, if possible, may therefore be of major therapeutic benefit. In the present study, we examined the effects of genistein and forskolin on duodenal mucosal HCO(3)(-) and Cl(-) secretion.

EXPERIMENTAL APPROACH:

Murine duodenal mucosal HCO(3)(-) and Cl(-) secretions were examined in vitro in Ussing chambers by the pH stat and short circuit current (I(sc)) techniques.

KEY RESULTS:

Genistein markedly stimulated duodenal HCO(3)(-) secretion and I(sc) in a dose-dependent manner in CFTR wild-type mice, but not in CFTR null mice. CFTR(inh)-172, a highly specific CFTR inhibitor, inhibited genistein-stimulated duodenal HCO(3)(-) secretion and I(sc) in wild-type mice. Genistein induced 59% net HCO(3)(-) increase and 123% net I(sc) increase over basal value, whereas forskolin, an activator of adenylate cyclase, induced 94% net HCO(3)(-) increase and 507% net I(sc) increase, indicating that, compared with forskolin, genistein induced a relatively high HCO(3)(-)/I(sc) ratio. Further data showed that CFTR HCO(3)(-)/Cl(-) conductance ratio was 1.05 after genistein stimulation, whereas after forskolin stimulation, the CFTR HCO(3)(-)/Cl(-) conductance ratio was 0.27.

CONCLUSIONS AND IMPLICATIONS:

Genistein stimulates duodenal HCO(3)(-) and Cl(-) secretion through CFTR, and has a relatively high selectivity for the CFTR HCO(3)(-) conductance, compared with forskolin. This may indicate the feasibility of selective targeting of the HCO(3)(-) conductance of the CFTR channels.

PMID:
19788494
PMCID:
PMC2782340
DOI:
10.1111/j.1476-5381.2009.00398.x
[Indexed for MEDLINE]
Free PMC Article

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