Novel short chain fatty acids restore chloride secretion in cystic fibrosis
- Division of Gastroenterology, Department of Medicine, University of Washington and VA Puget Sound Health Care System, Seattle, WA 98108 (United States)
- Cancer Center, Departments of Pediatrics, Medicine, Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118 (United States)
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 IB3-1 airway cells with {>=}1 mM ST7 or ST20 restored the ability of 100 {mu}M forskolin to stimulate an {sup 125}I{sup -} 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{sup -} channel regulated by CFTR. Thus, ST7 and ST20 offer treatment potential for CF caused by the {delta}F508 mutation.
- OSTI ID:
- 20798873
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 342, Issue 1; Other Information: DOI: 10.1016/j.bbrc.2006.01.127; PII: S0006-291X(06)00224-5; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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