Novel short chain fatty acids restore chloride secretion in cystic fibrosis.
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.
Division of Gastroenterology, Department of Medicine, University of Washington and VA Puget Sound Health Care System, Seattle, WA 98108, USA. T1Nguyen@u.washington.edu
Toan D
TD
Nguyen
Ug-Sung
US
Kim
Susan P
SP
Perrine
D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism*; D005232:Fatty Acids, Volatile / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007455:Iodine / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure
D002712:Chlorides; D005232:Fatty Acids, Volatile; D005576:Colforsin; D007455:Iodine