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Biochem Biophys Res Commun. 2006 Mar 31;342(1):245-52. Epub 2006 Feb 3.

Novel short chain fatty acids restore chloride secretion in cystic fibrosis.

Author information

1
Division of Gastroenterology, Department of Medicine, University of Washington and VA Puget Sound Health Care System, Seattle, WA 98108, USA. T1Nguyen@u.washington.edu

Abstract

Phenylalanine deletion at position 508 of the cystic fibrosis transmembrane conductance regulator (DeltaF508-CFTR), the most common mutation in cystic fibrosis (CF), causes a misfolded protein exhibiting partial chloride conductance and impaired trafficking to the plasma membrane. 4-Phenylbutyrate corrects defective DeltaF508-CFTR trafficking in vitro, but is not clinically efficacious. From a panel of short chain fatty acid derivatives, we showed that 2,2-dimethyl-butyrate (ST20) and alpha-methylhydrocinnamic acid (ST7), exhibiting high oral bioavailability and sustained plasma levels, correct the DeltaF508-CFTR defect. Pre-incubation (>or=6h) of CF IB3-1 airway cells with >or=1mM ST7 or ST20 restored the ability of 100microM forskolin to stimulate an (125)I(-) efflux. This efflux was fully inhibited by NPPB, DPC, or glibenclamide, suggesting mediation through CFTR. Partial inhibition by DIDS suggests possible contribution from an additional Cl(-) channel regulated by CFTR. Thus, ST7 and ST20 offer treatment potential for CF caused by the DeltaF508 mutation.

PMID:
16472777
DOI:
10.1016/j.bbrc.2006.01.127
[Indexed for MEDLINE]

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