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.
Nguyen
Toan D
TD
Division of Gastroenterology, Department of Medicine, University of Washington and VA Puget Sound Health Care System, Seattle, WA 98108, USA. T1Nguyen@u.washington.edu
Kim
Ug-Sung
US
Perrine
Susan P
SP
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