Role of Ca2+ in pancreatic cell death induced by alcohol metabolites.
Whereas alcohol itself, even in high concentrations, has little effect on the functional performance of isolated pancreatic acinar cells, non-oxidative metabolites (fatty acid ethyl esters [FAEE] and fatty acids [FA]) can cause Ca(2+)-dependent necrosis. The mechanism of action of FAEE has been investigated using a combination of patch clamp whole-cell current recording and Ca(2+) imaging. At low stimulation intensities, FAEE evoke repetitive short-lasting cytosolic Ca(2+) spikes, which are inhibited by caffeine, used as an inositol trisphosphate receptor antagonist. With more intense stimulation, sustained elevations of the cytosolic Ca(2+) concentration are observed, which can be prevented by pharmacological inhibition of the conversion of FAEE to FA. It is therefore the FA and not the FAEE that cause necrosis. The effect of FA cannot be blocked by inositol trisphosphate receptor antagonists. Fatty acids elicit a marked reduction in the cytosolic adenosine triphosphate (ATP) level. The patch clamp experiments show that the toxic sustained Ca(2+) signal generation induced by FA can be prevented by adding ATP to the cell interior. The toxic alcohol effects are principally due to FAEE produced under non-oxidative conditions and their subsequent conversion to FA. The FA-induced necrosis is Ca(2+)-dependent. The destructive sustained Ca(2+) signals are due to inhibition of mitochondrial function with failure of ATP generation.
Criddle
David N
DN
MRC Group, Physiological Laboratory, University of Liverpool, Liverpool, UK.
Sutton
Robert
R
Petersen
Ole H
OH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000378:metabolism* / Q000633:toxicity; D005227:Fatty Acids / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced*; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019512:Pancreatitis, Alcoholic / Q000378:metabolism* / Q000473:pathology*
D015220:Calcium Channels; D005227:Fatty Acids; D000431:Ethanol; D002118:Calcium