Ethanol metabolism and transcription factor activation in pancreatic acinar cells in rats.
OBJECTIVE
Ethanol metabolism by pancreatic acinar cells and the role of its metabolites in ethanol toxicity to the pancreas remain largely unknown. Here, we characterize ethanol metabolism in pancreatic acinar cells and determine the effects of ethanol metabolites on nuclear factor kappa B (NF-kappa B) and activator protein (AP)-1, transcription factors that are activated in pancreatitis and mediate expression of inflammatory molecules critical for this disease.


METHODS
We measured activities of fatty acid ethyl ester (FAEE) synthase and alcohol dehydrogenase (ADH), as well as accumulation of ethanol metabolites. We measured the effects of ethanol and its metabolites on NF-kappa B and AP-1 activation by using a gel shift assay.


RESULTS
Pancreas metabolizes ethanol via both oxidative and nonoxidative pathways. Acinar cells are the main source of ethanol metabolism in the pancreas. Compared with the liver, FAEE synthase activity in the pancreas is greater, whereas that of ADH is much less. FAEEs activated NF-kappa B and AP-1, whereas acetaldehyde inhibited NF-kappa B activation. Ethanol decreased NF-kappa B binding activity in acinar cells, which was potentiated by cyanamide.


CONCLUSIONS
Oxidative and nonoxidative ethanol metabolites regulate transcription factors differently in pancreatic acinar cells. Ethanol may regulate NF-kappa B and AP-1 positively or negatively, depending on which metabolic pathway's effect predominates. These regulatory mechanisms may play a role in ethanol toxicity to the pancreas.
Gukovskaya
Anna S
AS
Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles 90073, California, USA. agukovs@ucla.edu
Mouria
Michelle
M
Gukovsky
Ilya
I
Reyes
Chistopher N
CN
Kasho
Vladimir N
VN
Faller
Larry D
LD
Pandol
Stephen J
SJ
D000079:Acetaldehyde / Q000378:metabolism; D000085:Acetates / Q000378:metabolism; D000217:Acyltransferases / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000818:Animals; D002492:Central Nervous System Depressants / Q000493:pharmacokinetics*; D000431:Ethanol / Q000493:pharmacokinetics*; D005227:Fatty Acids / Q000378:metabolism; D066298:In Vitro Techniques; D016328:NF-kappa B / Q000378:metabolism*; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D000085:Acetates; D002492:Central Nervous System Depressants; D005227:Fatty Acids; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D000217:Acyltransferases; C043403:fatty acyl ethyl ester synthase; D000079:Acetaldehyde