Antibiotic accumulation and membrane trafficking in cystic fibrosis cells.
Cystic fibrosis (CF) results from mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) which is a regulated chloride channel. The deltaF508 mutation prevents the post-translational glycosylation and membrane insertion of the protein. Severe disease follows, with the formation of a viscous mucus and subsequent chronic bacterial infection of the lungs, necessitating frequent, and often long, periods of antibiotic treatment. The pharmacokinetics of antibiotics in CF patients are abnormal, with lower blood serum levels and higher clearance rates which have never been satisfactorily explained. We found that accumulation of gentamicin in nasal polyp tissue non-CF cells was subject to regulation by the effectors and inhibitors of CFTR function; regulation was lost in deltaF508 CF cells and accumulation was more than doubled because of the inhibition of exocytosis.
Quesnel
L B
LB
School of Biological Sciences, University of Manchester, UK.
Jaran
A S
AS
Braganza
J M
JM
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000266:Adenylyl Imidodiphosphate / Q000494:pharmacology; D000328:Adult; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000493:pharmacokinetics; D005839:Gentamicins / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009298:Nasal Polyps; D013873:Thionucleotides / Q000494:pharmacology
C505032:CFTR protein, human; D005839:Gentamicins; D013873:Thionucleotides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D000266:Adenylyl Imidodiphosphate; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; C080501:1-(5-isoquinolinylsulfonyl)-3-methylpiperazine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D016650:Fluorescein-5-isothiocyanate; D015056:1-Methyl-3-isobutylxanthine