Ketoconazole activates Cl- conductance and blocks Cl- and fluid absorption by cultured cystic fibrosis (CFPAC-1) cells.
The role of arachidonic acid metabolites in the regulation of apical cell membrane Cl- conductance and transepithelial transport of fluid and Cl- by cultured pancreatic cells from cystic fibrosis (CFPAC-1) and corrected (PAC-1) cell lines was evaluated by the use of inhibitors. CFPAC-1 cells did not exhibit an apical membrane Cl- conductance, absorbed Cl- and fluid, and did not respond to stimulation or inhibition of cAMP action. PAC-1 cells exhibited a cAMP-responsive apical Cl- conductance, which was blocked by indomethacin, a cyclooxygenase inhibitor. Ketoconazole, an epoxygenase inhibitor, had virtually no effects on PAC-1 cell Cl- conductance but caused CFPAC-1 cells to develop a cAMP-insensitive Cl- conductance, blocked Cl- and fluid absorption, and reduced transepithelial electrical resistance. Ketoconazole treatment effectively reversed the cystic fibrosis defect in these cultured cells.
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National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
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Spring
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D000042:Absorption; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007654:Ketoconazole / Q000494:pharmacology*; D009637:Masoprocol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011335:Proadifen / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014162:Transfection
C505032:CFTR protein, human; D018118:Chloride Channels; D002712:Chlorides; D007473:Ion Channels; D008565:Membrane Proteins; D013873:Thionucleotides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D009637:Masoprocol; D011335:Proadifen; D000242:Cyclic AMP; D007654:Ketoconazole; D007213:Indomethacin