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Role of Ca2+ in pancreatic cell death induced by alcohol metabolites

Criddle, David N., Sutton, Robert and Petersen, Ole Holger 2006. Role of Ca2+ in pancreatic cell death induced by alcohol metabolites. Journal of Gastroenterology and Hepatology 21 (Sup.s3) , S14-S17. 10.1111/j.1440-1746.2006.04577.x

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Abstract

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 Ca2+-dependent necrosis. The mechanism of action of FAEE has been investigated using a combination of patch clamp whole-cell current recording and Ca2+ imaging. At low stimulation intensities, FAEE evoke repetitive short-lasting cytosolic Ca2+ spikes, which are inhibited by caffeine, used as an inositol trisphosphate receptor antagonist. With more intense stimulation, sustained elevations of the cytosolic Ca2+ 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 Ca2+ 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 Ca2+-dependent. The destructive sustained Ca2+ signals are due to inhibition of mitochondrial function with failure of ATP generation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Uncontrolled Keywords: adenosine triphosphate; alcohol metabolites; calcium toxicity; fatty acid ethyl esters; fatty acids; necrosis
Publisher: Wiley-Blackwell
ISSN: 0815-9319
Last Modified: 04 Jun 2017 06:38
URI: http://orca-mwe.cf.ac.uk/id/eprint/63118

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