Biochemical and Biophysical Research Communications, Vol.342, No.1, 245-252, 2006
Novel short chain fatty acids restore chloride secretion in cystic fibrosis
Phenylalanine deletion at position 508 of the cystic fibrosis transmembrane conductance regulator (Delta F508-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 Delta F508-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 Delta F508-CFTR defect. Pre-incubation (>= 6 h) of CF 1B3-1 airway cells with >= 1 mM ST7 or ST20 restored the ability of 100 mu M forskolin to stimulate an I-125(-) 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 CI- channel regulated by CFTR. Thus, ST7 and ST20 offer treatment potential for CF caused by the Delta F508 mutation. (c) 2006 Elsevier Inc. All rights reserved.