Ethanol metabolism and transcription factor activation in pancreatic acinar cells in rats.

BACKGROUND & AIMS 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. CONCLUSION 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.

[1]  S. Pandol,et al.  Localized pancreatic NF-kappaB activation and inflammatory response in taurocholate-induced pancreatitis. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[2]  I. Rusyn,et al.  Development of an animal model of chronic alcohol-induced pancreatitis in the rat. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[3]  P. Tak,et al.  NF-κB: a key role in inflammatory diseases , 2001 .

[4]  E. Livingston,et al.  Activation of pancreatic acinar cells on isolation from tissue: cytokine upregulation via p38 MAP kinase. , 2000, American journal of physiology. Cell physiology.

[5]  S. Pandol,et al.  Cerulein upregulates ICAM-1 in pancreatic acinar cells, which mediates neutrophil adhesion to these cells. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[6]  R. Schmid,et al.  NF-κB/Rel/IκB: Implications in gastrointestinal diseases , 2000 .

[7]  J. Neoptolemos,et al.  Inflammatory mediators in acute pancreatitis , 2000, The Journal of pathology.

[8]  R. Wisdom,et al.  AP-1: one switch for many signals. , 1999, Experimental cell research.

[9]  S. Pandol,et al.  Ethanol diet increases the sensitivity of rats to pancreatitis induced by cholecystokinin octapeptide. , 1999, Gastroenterology.

[10]  R. Schmid,et al.  Caerulein-induced NF-κB/Rel activation requires both Ca2+ and protein kinase C as messengers. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[11]  A. Nanji,et al.  Acetaldehyde prevents nuclear factor-kappa B activation and hepatic inflammation in ethanol-fed rats. , 1999, Laboratory investigation; a journal of technical methods and pathology.

[12]  B. Han,et al.  Cholecystokinin induction of mob-1 chemokine expression in pancreatic acinar cells requires NF-κB activation. , 1999, American journal of physiology. Cell physiology.

[13]  A. Nanji,et al.  Acetaldehyde Inhibits NF-κB Activation through IκBα Preservation in Rat Kupffer Cells , 1998 .

[14]  S. Pandol,et al.  Early NF-κB activation is associated with hormone-induced pancreatitis. , 1998, American journal of physiology. Gastrointestinal and liver physiology.

[15]  T. Shibamoto,et al.  Quantitative analysis of acetaldehyde in whole blood from human and various animals by gas chromatography. , 1998, Journal of chromatography. B, Biomedical sciences and applications.

[16]  M. Korsten,et al.  Metabolism of ethanol by rat pancreatic acinar cells. , 1998, The Journal of laboratory and clinical medicine.

[17]  S. Pandol,et al.  Cerulein activates NF-κB and AP-1 in isolated pancreatic acinar cells , 1998 .

[18]  S. Schenker,et al.  Alcohol and the pancreas. , 1998, Recent developments in alcoholism : an official publication of the American Medical Society on Alcoholism, the Research Society on Alcoholism, and the National Council on Alcoholism.

[19]  J. Norman The role of cytokines in the pathogenesis of acute pancreatitis. , 1998, American journal of surgery.

[20]  S. Pandol,et al.  Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-alpha. Role in regulating cell death and pancreatitis. , 1997, The Journal of clinical investigation.

[21]  K. Lewandrowski,et al.  Pancreatic injury in rats induced by fatty acid ethyl ester, a nonoxidative metabolite of alcohol. , 1997, Gastroenterology.

[22]  S. Ohmori,et al.  Determination of acetaldehyde in biological samples by gas chromatography with electron-capture detection. , 1997, Journal of chromatography. B, Biomedical sciences and applications.

[23]  M. Karin,et al.  Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. , 1997, The New England journal of medicine.

[24]  C. Scheidereit,et al.  The NF-κB/Rel and IκB gene families: mediators of immune response and inflammation , 1996, Journal of Molecular Medicine.

[25]  K. Kitson,et al.  Ethanol and acetaldehyde metabolism: past, present, and future. , 1996, Alcoholism, clinical and experimental research.

[26]  P. Braquet,et al.  The role of neutrophils and platelet-activating factor in mediating experimental pancreatitis. , 1996, Gastroenterology.

[27]  K. Mak,et al.  Metabolism of alcohol by human gastric cells: relation to first-pass metabolism. , 1996, Gastroenterology.

[28]  D. Brenner,et al.  Detection of alpha-hydroxyethyl free radical adducts in the pancreas after chronic exposure to alcohol in the rat. , 1996, Molecular pharmacology.

[29]  M. Franz,et al.  Acute pancreatitis induces intrapancreatic tumor necrosis factor gene expression. , 1995, Archives of surgery.

[30]  P. Fabri,et al.  Decreased Mortality of Severe Acute Pancreatitis After Proximal Cytokine Blockade , 1995, Annals of surgery.

[31]  G. Dickersin,et al.  Fatty acid ethyl esters decrease human hepatoblastoma cell proliferation and protein synthesis. , 1995, Gastroenterology.

[32]  M. Laposata,et al.  Mode of transport of fatty acid to endothelial cells influences intracellular fatty acid metabolism. , 1995, Journal of lipid research.

[33]  A. Andrén-sandberg,et al.  Prognosis of chronic pancreatitis: an international multicenter study. International Pancreatitis Study Group. , 1994, The American journal of gastroenterology.

[34]  H. K. Bojes,et al.  Inactivation of Kupffer cells prevents early alcohol‐induced liver injury , 1994, Hepatology.

[35]  T. Tsujita,et al.  The synthesis of fatty acid ethyl ester by carboxylester lipase. , 1994, European journal of biochemistry.

[36]  C. Lieber Alcohol and the liver: 1994 update. , 1994, Gastroenterology.

[37]  J. de Jersey,et al.  Biosynthesis and possible pathological significance of fatty acid ethyl esters. , 1994, Alcohol and alcoholism (Oxford, Oxfordshire). Supplement.

[38]  M. Apte,et al.  Fatty acid ethyl esters increase rat pancreatic lysosomal fragility. , 1993, The Journal of laboratory and clinical medicine.

[39]  R. Vonk,et al.  The role of glutathione in bile secretion of endogenous trace elements in rats. , 1993, The Journal of laboratory and clinical medicine.

[40]  T. Badger,et al.  Episodic excretion of ethanol during chronic intragastric ethanol infusion in the male rat: continuous vs. cyclic ethanol and nutrient infusions. , 1993, The Journal of pharmacology and experimental therapeutics.

[41]  C. Lieber,et al.  Alcohol and the Liver , 1992 .

[42]  C. Hirayama,et al.  Nonoxidative metabolism of ethanol in the pancreas; implication in alcoholic pancreatic damage. , 1990, Biochemical pharmacology.

[43]  M. Boleda,et al.  Role of extrahepatic alcohol dehydrogenase in rat ethanol metabolism. , 1989, Archives of biochemistry and biophysics.

[44]  J. Wands,et al.  Ethanol-induced inhibition of liver cell function: I. Effect of ethanol on hormone stimulated hepatocyte DNA synthesis and the role of ethanol metabolism. , 1988, Alcoholism, clinical and experimental research.

[45]  H. Tsukamoto,et al.  Potentiation of ethanol-induced pancreatic injury by dietary fat. Induction of chronic pancreatitis by alcohol in rats. , 1988, The American journal of pathology.

[46]  H. Tsukamoto,et al.  Ethanol‐induced liver fibrosis in rats fed high fat diet , 1986, Hepatology.

[47]  E. Laposata,et al.  Presence of nonoxidative ethanol metabolism in human organs commonly damaged by ethanol abuse. , 1986, Science.

[48]  H. Tsukamoto,et al.  Cyclical pattern of blood alcohol levels during continuous intragastric ethanol infusion in rats. , 1985, Alcoholism, clinical and experimental research.

[49]  L. G. Lange,et al.  Nonoxidative ethanol metabolism in rabbit myocardium: purification to homogeneity of fatty acyl ethyl ester synthase. , 1984, Biochemistry.

[50]  S. Wickramasinghe,et al.  Investigations into the production of acetate from ethanol by human blood and bone marrow cells in vitro. , 1983, Acta haematologica.

[51]  A. Estival,et al.  Ethanol metabolism by the rat pancreas. , 1981, Toxicology and applied pharmacology.

[52]  M. Krieger,et al.  Replacement of endogenous cholesteryl esters of low density lipoprotein with exogenous cholesteryl linoleate. Reconstitution of a biologically active lipoprotein particle. , 1978, The Journal of biological chemistry.

[53]  R. Havel,et al.  The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. , 1955, The Journal of clinical investigation.