Linkage of oxidative and nonoxidative ethanol metabolism in the pancreas and toxicity of nonoxidative ethanol metabolites for pancreatic acinar cells.
BACKGROUND
Alcohol abuse is a major cause of pancreatic damage. Recent experimental evidence suggests that fatty acid ethyl esters (FAEE), nonoxidative ethanol metabolites, injure pancreatic acinar cells. Linkage between oxidative and nonoxidative metabolism of ethanol in the pancreas may contribute to increased FAEE levels.


METHODS
To study the association between oxidative and nonoxidative ethanol metabolism, FAEE concentration and FAEE synthase activity in rat pancreatic and liver homogenates incubated with ethanol were evaluated with and without inhibitors of oxidative ethanol metabolism. For toxicity studies, trypsinogen activation peptide synthesis as a measure of pancreatic cell injury was quantitated in unstimulated and cerulein-stimulated isolated pancreatic acinar cells incubated with ethanol or FAEE.


RESULTS
Inhibition of oxidative ethanol metabolism results in a 2- to 3-fold increase in nonoxidative ethanol metabolism to FAEE in pancreas and in liver. Both ethanol and FAEE induce increased intracellular trypsinogen activation by more than 50% in the presence of physiologic concentrations of cerulein in vitro.


CONCLUSIONS
These findings demonstrate that the inhibition of oxidative ethanol metabolism results in an increase in flux through the nonoxidative pathway and support the proposition that alcohol-induced pancreatic injury is mediated at least in part by FAEE, which are important products of pancreatic ethanol metabolism.
Werner
J
J
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St., Boston, MA 02114.
Saghir
M
M
Fernandez-del Castillo
C
C
Warshaw
A L
AL
Laposata
M
M
D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D002766:Cholecystokinin / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism* / Q000633:toxicity; D008297:Male; D010084:Oxidation-Reduction; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000431:Ethanol; D002766:Cholecystokinin; D000217:Acyltransferases; C043403:fatty acyl ethyl ester synthase