Ethanol and its non-oxidative metabolites profoundly inhibit CFTR function in pancreatic epithelial cells which is prevented by ATP supplementation.
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.
Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
L
L
Judák
P
P
Hegyi
Z
Z
Rakonczay
J
J
Maléth
M A
MA
Gray
V
V
Venglovecz
D000079:Acetaldehyde / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D010183:Pancreatic Ducts / Q000166:cytology
D005229:Fatty Acids, Monounsaturated; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C008757:palmitoleic acid; D000431:Ethanol; D000255:Adenosine Triphosphate; D000079:Acetaldehyde