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Published ahead of print on June 10, 2004, doi:10.1165/rcmb.2002-0086OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 3, September 2004, 351-357

A more recent version of this article appeared on September 1, 2004
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Submitted on June 28, 2002
Revised on June 8, 2004

Modulation of {Delta}F508 CFTR trafficking and function with 4-PBA and flavonoids

Meerana Lim1, Karen McKenzie1, Alexandra D Floyd1, Edwin Kwon1, and Pamela L Zeitlin1*

1 Department of Pediatrics, The Johns Hopkins University, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: pzeitlin{at}jhmi.edu.

Over 70% of patients with cystic fibrosis have the {Delta}F508 mutation. This protein is a partially functional chloride channel that is prematurely degraded in the endoplasmic reticulum. Specific members of the flavonoid class of compounds have been shown to increase chloride conductance of wild-type and {Delta}F508 cystic fibrosis transmembrane regulator (CFTR). Although flavonoid effects on CFTR processing are unknown, evidence of effects on heat shock proteins, specifically those which have been shown to interact with CFTR led us to believe there would be an effect on CFTR processing through modulation of CFTR-chaperone interactions. We sought to determine (1) the effect of apigenin, genistein, kaempferol and quercetin on CFTR processing in IB3-1 cells (F508/W1282X) and (2) whether sequential treatment with 4-phenylbutyrate to increase CFTR processing and flavonoid to directly stimulate CFTR would increase chloride conductance. Our results show no significant effect on CFTR processing as measured by immunoblotting with 1µM or 5 µM concentrations of apigenin, genistein, kaempferol or quercetin. However, despite no effect on CFTR processing as determined by immunoblot, immunofluorescence demonstrated a favorable change in the intra-cellular distribution of CFTR with 24 hour treatments of apigenin, kaempferol and genistein. Furthermore, we observed an increase in chloride conductance as measured by chloride efflux in cells that were treated for 24 hours with 4-PBA and then assayed with forskolin and 1µM or 5µM genistein, and also with cells treated for 24 hrs with either 4-PBA, 5 µM apigenin, or 1 µM quercetin. Thus a combination of chronic treatment with 4-PBA or select flavonoids, followed by acute flavonoid exposure may be beneficial in CF.




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