Ethanol and its non-oxidative metabolites profoundly inhibit CFTR function in pancreatic epithelial cells which is prevented by ATP supplementation
| Autor: | Viktória Venglovecz, Linda Judák, Zoltán Rakonczay, Michael A. Gray, József Maléth, Péter Hegyi |
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| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Physiology Metabolite Guinea Pigs Clinical Biochemistry Action Potentials Cystic Fibrosis Transmembrane Conductance Regulator Acetaldehyde Oxidative phosphorylation Fatty Acids Monounsaturated Pathogenesis chemistry.chemical_compound Adenosine Triphosphate Cell Line Tumor Physiology (medical) Internal medicine medicine Animals Humans Secretion Receptor Cells Cultured Ethanol biology Pancreatic Ducts Epithelial Cells medicine.disease Cystic fibrosis transmembrane conductance regulator Endocrinology chemistry biology.protein Pancreatitis Intracellular |
| Zdroj: | Pflügers Archiv - European Journal of Physiology. 466:549-562 |
| ISSN: | 1432-2013 0031-6768 |
| Popis: | Excessive alcohol consumption is a major cause of acute pancreatitis, but the mechanism involved is not well understood. Recent investigations suggest that pancreatic ductal epithelial cells (PDECs) help defend the pancreas from noxious agents such as alcohol. Because the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel plays a major role in PDEC physiology and mutated CFTR is often associated with pancreatitis, we tested the hypothesis that ethanol affects CFTR to impair ductal function. Electrophysiological studies on native PDECs showed that ethanol (10 and 100 mM) increased basal, but reversibly blocked, forskolin-stimulated CFTR currents. The inhibitory effect of ethanol was mimicked by its non-oxidative metabolites, palmitoleic acid ethyl ester (POAEE) and palmitoleic acid (POA), but not by the oxidative metabolite, acetaldehyde. Ethanol, POAEE and POA markedly reduced intracellular ATP (ATPi) which was linked to CFTR inhibition since the inhibitory effects were almost completely abolished if ATPi depletion was prevented. We propose that ethanol causes functional damage of CFTR through an ATPi-dependent mechanism, which compromises ductal fluid secretion and likely contributes to the pathogenesis of acute pancreatitis. We suggest that the maintenance of ATPi may represent a therapeutic option in the treatment of the disease. |
| Databáze: | OpenAIRE |
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