Abstract
Cystic fibrosis (CF), due to mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), exhibits a wide range of disease severity, even among ΔF508 homozygous patients, and the mechanisms of this variability have yet to be elucidated. In view of the close structural homology and possible functional overlap between CFTR and Multidrug Resistance-associated Proteins (MRPs), MRPs were investigated as potentially relevant factors in CF pathophysiology. MRP1-5 gene expression was analyzed in nasal respiratory epithelial cells from ΔF508 homozygous patients (n = 19) and control subjects (n = 20) using semiquantitative RT-PCR. Significantly lower MRP1 and MRP5 transcript levels were found in CF patients than in control subjects. MRP1 and MRP5 transcript levels were strongly correlated (r = 0.71). In CF patients, low MRP1 transcript levels were associated with more severe disease as assessed by the Shwachman score. A relation was also observed between MRP1 levels and presence of a cAMP-independent chloride conductive pathway, as determined by a halide-sensitive fluorescent assay. These results suggest that MRPs, especially MRP1, might play a role in CF phenotype and might therefore constitute a target for a novel pharmacotherapy of CF.
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Abbreviations
- CF:
-
cystic fibrosis
- CFTR:
-
cystic fibrosis transmembrane conductance regulator
- dNTP:
-
deoxynucleoside triphosphate
- FEV1:
-
forced expiratory volume
- FVC:
-
forced vital capacity
- MDR1:
-
multidrug transporter 1
- Pgp:
-
P-glycoprotein
- MRPs:
-
multidrug resistance-associated proteins
- RT-PCR:
-
reverse transcription-PCR
- SPQ:
-
6-methoxy-N-3-sulfopropylquinolinium
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The authors thank C. Durrant and J. Lehmann-Che for skillful assistance and J.H. Calvet for helpful discussion.
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Supported by grants from “ABCF Protéines” Association, “Vaincre la Mucoviscidose” Association and by Université Paris VI.
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Hurbain, I., Sermet-Gaudelus, I., Vallée, B. et al. Evaluation of MRP1-5 Gene Expression in Cystic Fibrosis Patients Homozygous for the ΔF508 Mutation. Pediatr Res 54, 627–634 (2003). https://doi.org/10.1203/01.PDR.0000090926.16166.3F
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DOI: https://doi.org/10.1203/01.PDR.0000090926.16166.3F
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