Nonoxidative metabolism of ethanol in the pancreas; implication in alcoholic pancreatic damage

Hamamoto, Tetsuro; Yamada, Sadako; Hirayama, Chisato

doi:10.1016/0006-2952(90)90022-d

Cited by 65 publications

(31 citation statements)

References 20 publications

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“…Hamamoto et al (10) have shown that fatty acid ethyl ester synthase activity is much higher in pancreas compared with liver (1,348 vs. 23 nmol/h per mg protein). According to Haber et al (9), the rate of oxidative metabolism of ethanol in cultured rat PAC was 21-fold higher than that of nonoxidative metabolism.…”

Section: Discussionmentioning

confidence: 98%

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Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL)

Siech

Zhou

Zhou³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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MG. Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL). Am J Physiol Gastrointest Liver Physiol 297: G1163-G1171, 2009. First published September 24, 2009 doi:10.1152/ajpgi.90468.2008.-Mechanisms leading to acute pancreatitis after a fat-enriched meal combined with excess alcohol are incompletely understood. We have studied the effects of alcohol and fat (VLDL) on pancreatic acinar cell (PAC) function, oxidative stress, and repair mechanisms by pancreatic stellate cells (PSC) leading to fibrogenesis. To do so, PAC (rat) were isolated and cultured up to 24 h. Ethanol and/or VLDL were added to PAC. We measured PAC function (amylase, lipase), injury (lactic dehydrogenase), apoptosis (TUNEL, Apo2.7, annexin V binding), oxidative stress, and lipid peroxidation (conjugated dienes, malondialdehyde, chemoluminescence); we also measured PSC proliferation (bromodeoxyuridine incorporation), matrix synthesis (immunofluorescence of collagens and fibronectin, fibronectin immunoassay), and fatty acids in PAC supernatants (gas chromatography). Within 6 h, cultured PAC degraded and hydrolyzed VLDL completely. VLDL alone (50 g/ml) and in combination with alcohol (0.2, 0.5, and 1% vol/vol) induced PAC injury (LDL, amylase, and lipase release) within 2 h through generation of oxidative stress. Depending on the dose of VLDL and alcohol, apoptosis and/or necrosis were induced. Antioxidants (Trolox, Probucol) reduced the cytotoxic effect of alcohol and VLDL. Supernatants of alcohol/VLDL-treated PAC stimulated stellate cell proliferation and extracellular matrix synthesis. We concluded that, in the presence of lipoproteins, alcohol induces acinar cell injury. Our results provide a biochemical pathway for the clinical observation that a fat-enriched meal combined with excess alcohol consumption can induce acinar cell injury (acute pancreatitis) followed by repair mechanisms (proliferation and increased matrix synthesis in PSC).ethanol; free radicals; pancreas THE MECHANISM OF ALCOHOLIC PANCREATITIS is incompletely understood. Despite the fact that about 40% of acute pancreatitis and 70% of chronic pancreatitis in humans are induced by alcohol, most alcoholics will never be affected by any of these diseases. As calculated by Ammann et al. (1), only 5% of all alcohol abusers will develop alcoholic pancreatitis. Interestingly enough, this can also be observed in setups with animals where acute pancreatitis cannot be induced by alcohol itself (8,15,25). Therefore, additional factors accompanying alcohol intake must be coresponsible for the induction of the disease. Some of these cofactors such as stimulation of pancreatic secretion and/or obstruction of pancreatic outflow have been experimentally observed by us and others (8,12,25,26).Clinical experience has taught us that a large number of patients presenting an acute event of alcoholic pancreatitis have drunk lots of alcohol together with an opulent (fat enriched) meal the day before onset of the disease. In the present ...

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Section: Discussionmentioning

confidence: 98%

“…Pancreatic acinar cells (PAC) also metabolize ethanol by oxidative (10,18) and nonoxidative pathway (9). We offered the hypothesis that exposure of PAC to ethanol induces the production of free radicals, which could further react with double bonds of unsaturated fatty acids, generating lipid peroxides.…”

mentioning

confidence: 99%

Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL)

Siech

Zhou

Zhou³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Following ethanol exposure, it has been shown that FAEEs are transported in the blood [9] and taken up by the pancreas from the circulation [10,21]. Homogenates of pancreatic tissue possess FAEE synthetic activity [7,13,22]. However, studies using tissue homogenates have often used 'unphysiological' concentrations of ethanol and exogenous free fatty acids.…”

Section: Discussionmentioning

confidence: 99%

“…With respect to the non-oxidative pathway, FAEEs have been demonstrated in both human [6] and rat [7] pancreas after ethanol consumption. A postmortem study involving subjects intoxicated at the time of death revealed higher levels of FAEEs in the pancreas than in any other parenchymal organ [6].…”

Section: Introductionmentioning

confidence: 99%

Non-Oxidative Metabolism of Ethanol by Rat Pancreatic Acini

et al. 2004

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“…18 Recently, an important mechanism whereby alcohol may induce Ca 2 þ -dependent necrotic acinar cell death has been identified. 12 Fatty acid ethyl esters (FAEEs), non-oxidative metabolites of ethanol, are generated at higher concentrations within the pancreas than any other organ, [77][78][79] and unlike ethanol per se, are able to induce experimental pancreatitis in vivo. 80 Non-oxidative ethanol metabolites induce persistent, global, cytosolic Ca 2 þ signals in a concentration-dependent manner, 11 initiated via IP 3 receptor-mediated Ca 2 þ release and sustained by depolarisation of mitochondria, 12 the organelle at which FAEE accumulation and hydrolysis to fatty acids (FA) is thought to occur.…”

Section: 75mentioning

confidence: 99%