Role of alcohol metabolism in alcoholic pancreatitis.
Metabolism of ethanol by acinar and other pancreatic cells and the consequent generation of toxic metabolites are postulated to play an important role in the development of alcohol-related acute and chronic pancreatic injury. Studies using cultured pancreatic acinar cells and isolated pancreatic acini have established that (i) the pancreas can metabolize ethanol via the oxidative pathway involving the enzymes alcohol dehydrogenase (ADH) and possibly cytochrome P4502E1 (although the role of the latter remains to be fully delineated) as well as the nonoxidative pathway [involving fatty acid ethyl ester (FAEE) synthases] and (ii) the oxidative pathway (which generates acetaldehyde) is quantitatively greater than the nonoxidative pathway, which yields FAEEs. Most recently, pancreatic stellate cells (PSCs) (implicated in pancreatic fibrogenesis) have been reported to exhibit ADH activity, suggesting that the capacity of the pancreas to metabolize ethanol may reside not only in parenchymal (acinar) cells but also in nonparenchymal cells. Polymorphisms/mutations of ethanol metabolizing enzymes have been examined to determine whether they may confer individual susceptibility to alcoholic pancreatitis. However, no association has been demonstrated between ADH and CYP2E1 polymorphisms and the predisposition to alcoholic pancreatitis. Other candidate factors that remain to be studied include polymorphisms of FAEE synthetic enzymes and proteins relevant to antioxidant pathways in the cell. Injury to the pancreas due to its capacity to metabolize ethanol may be mediated by direct effects of both acetaldehyde and FAEEs and by alterations induced within the cells during ethanol metabolism, such as changes in the intracellular redox state and the generation of oxidant stress.
Wilson
J S
JS
Pancreatic Research Group, Department of Gastroenterology, Bankstown-Lidcombe and Liverpool Hospitals and The University of New South Wales, Sydney, Australia. js.wilson@unsw.edu.au
Apte
M V
MV
D000426:Alcohol Dehydrogenase / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D019512:Pancreatitis, Alcoholic / Q000139:chemically induced / Q000378:metabolism*
D000431:Ethanol; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1