Effect of chronic alcohol administration on the exocrine pancreas after jejunoileal bypass in the rat

To determine whether intestinal bypass operation and alcohol administration exerted a synergistic effect on pancreatic enzyme composition and morphology, adult rats were submitted either to a sham-operation or to a 90 per cent jejunoileal bypass. Two weeks after the operation, the rats received a 15 per cent solution of ethanol in drinking fluid during a period of four weeks while controls received water. In sham-operated animals, alcohol had no effect on pancreatic weight or its total content in protein and amylase. The general structural and ultrastructural aspect remained unchanged except for the presence of a few mixed acinar-islet cells. Bypass operation alone induced a significant decrease in amylase content while the population of zymogen granules was reduced. Parallely, lipid droplets deposited within acinar cells. Alcohol administered in bypassed animals exerted a synergistic effect on fat accumulation in pancreatic acinar cells but had no effect on other biochemical and morphological parameters.     

Irreversible Exocrine Pancreatic Insufficiency in Alcoholic Rats Without Chronic Pancreatitis After Alcohol Withdrawal

Background: Long‐term alcohol consumption alone did not cause chronic pancreatitis (CP) but impaired exocrine pancreatic function. This study is to explore the reversibility of exocrine pancreatic insufficiency in the abstinent rats and its mechanism. Methods: Forty‐eight healthy male Wistar rats were divided randomly into 4 groups: 6‐month control, 6‐month ethanol, 9‐month control, and 9‐month ethanol + withdrawal. Morphological changes of pancreatic acinar cells were observed. Pancreatic amylase and lipase were measured using an automatic biochemical analyzer. Free fatty acid (FFA) in rat intestinal chyme was measured. Cholecystokinin (CCK) levels were determined by radioimmunoassay. The expression of CCK‐A receptors was quantitatively analyzed by Western blot. Results: Alcohol‐induced ultramicrostructure changes of pancreatic acinar cells, including lipid droplets, myelinoid inclusion bodies, dilated rough endoplasmic reticulums, and diminished zymogen granules, were not attenuated after alcohol abstinence. The outputs of amylase and lipase, FFA content in intestinal chyme, and the intestinal and the pancreatic CCK levels in rats were reduced after chronic alcohol intake and were still lower than the control after cessation of alcohol use. Chronic ethanol intake or abstinence did not induce any change in the expression of CCK‐A receptors. Conclusions: Exocrine pancreatic insufficiency was irreversible in alcoholic rats without CP after alcohol withdrawal. It may be attributed to reduced pancreatic CCK, long‐standing fatty infiltration, ultramicrostructure injuries in pancreatic acinar cells, and aging.     

Effects of prolonged ethanol intake and malnutrition on rat pancreas.

Nutritional factors, especially the protein and fat content of the diet, may change pancreatic morphology after ethanol induced injury. This study was performed to delineate the combined effects of a low fat diet and longterm ethanol ingestion on the rat pancreas. Male Sprague-Dawley rats were maintained with five different diets for 12 weeks and the pancreas removed on the day they were killed. Rats fed a very low fat diet without ethanol (5% of total calories as lipid) developed malnutrition, pancreatic steatosis, and reduction in zymogen granules content. Animals fed a 35% lipid diet with ethanol also developed pancreatic steatosis but changes in zymogen granules content were not detected. Both malnutrition and longterm ethanol consumption increased pancreatic cholesterol ester content, and their effects were additive. Pancreatic steatosis was accompanied with hypercholesterolaemia. Amylase, lipase, and cholesterol esterase content were reduced in malnourished rats; but longterm ethanol ingestion, regardless of the nutritional state, increased lipase content and decreased amylase. It is suggested that high serum cholesterol concentrations and increased pancreatic lipase activity could cause accumulation of cholesterol esters in acinar cells. Fat accumulation in the pancreas has been reported as the earliest histopathological feature in alcoholic patients and may be responsible for cytotoxic effects on the acinar cells at the level of the cell membrane. Although it is difficult to extrapolate results in this animal study to the human situation, the results presented in this work might explain the higher incidence of pancreatitis is malnourished populations as well as in alcoholic subjects that is reported in dietary surveys.     

Changes in zymogen granule membrane and pancreatic juice after supramaximal stimulation with caerulein in the rat

Summary Pancreatic exocrine secretion was stimulated supramaximally with an intravenous infusion of 10 μg/kg of body weight of caerulein for 10 min in four rats. Two animals were killed immediately, and two animals 120 min after the cessation of the caerulein infusion. In specimens fixed immediately after the caerulein infusion, there were irregular electron lucent structures that resembled zymogen granules and were associated with bristle-coated membranes, coated pits and coated vesicles. Two hours after the caerulein infusion there were large vacuoles that contained amorphous or membranous material and cell organelles in acinar cells. The HPLC-analysis of pancreatic juice revealed two new peaks after caerulein injection. It was concluded that supramaximal caerulein stimulation prevents normal maturation and discharge of zymogen granules leading to altered membrane recycling of secretory granules in acinar cells and to the appearance of abnormal secretory products in pancreatic juice. The novel ultrastructural findings of this study, the bristle-coated membranes and the coated pits in the membrane of dilated zymogen granules, may be related to the exceedingly high dose of caerulein administered.     

Changes in zymogen granule membrane and pancreatic juice after supramaximal stimulation with caerulein in the rat

Pancreatic exocrine secretion was stimulated supramaximally with an intravenous infusion of 10 micrograms/kg of body weight of caerulein for 10 min in four rats. Two animals were killed immediately, and two animals 120 min after the cessation of the caerulein infusion. In specimens fixed immediately after the caerulein infusion, there were irregular electron lucent structures that resembled zymogen granules and were associated with bristle-coated membranes, coated pits and coated vesicles. Two hours after the caerulein infusion there were large vacuoles that contained amorphous or membranous material and cell organelles in acinar cells. The HPLC-analysis of pancreatic juice revealed two new peaks after caerulein injection. It was concluded that supramaximal caerulein stimulation prevents normal maturation and discharge of zymogen granules leading to altered membrane recycling of secretory granules in acinar cells and to the appearance of abnormal secretory products in pancreatic juice. The novel ultrastructural findings of this study, the bristle-coated membranes and the coated pits in the membrane of dilated zymogen granules, may be related to the exceedingly high dose of caerulein administered.     

Morphometric study of the rat exocrine pancreas after diversion of bile and pancreatic juice from the intestine

The effects of 6 h of diversion of bile and pancreatic juice from the intestine on the ultrastructure of rat pancreatic acinar cells were studied by morphometric procedures. After diversion the volume of zymogen granules decreased markedly, representing a reduction of 77%. The volume of autophagic vacuoles increased twofold after diversion. The volume of rough endoplasmic reticulum and Golgi apparatus was not different from that of control. It has been proved by electron microscopic morphometry that the degree of reduction of zymogen granules was similar to that after stimulation by exogenous cholecystokinin or introduction of trypsin inhibitor to the duodenum. This suggests that hypersecretion caused by diversion is due to failure of a negative feedback regulation normally induced by proteases found in pancreatic juice. An increased number of autophagic vacuoles suggests an increase of organelle turnover due to heightened secretory activity of acinar cells.     

Chronic ethanol consumption increases the fragility of rat pancreatic zymogen granules.

Intracellular activation of pancreatic digestive enzymes by lysosomal hydrolases is thought to be an early event in the pathogenesis of pancreatic injury. As ethanol excess is an important association of pancreatitis, experimental work has been directed towards exploring possible mechanisms whereby ethanol may facilitate contact between inactive digestive enzyme precursors and lysosomal enzymes. The aim of this study was to find out if chronic ethanol administration increases the fragility of rat pancreatic zymogen granules. Sixteen male Sprague-Dawley rats were pair fed ethanol and control liquid diets for four weeks. Zymogen granule fragility was then assessed in pancreatic homogenate by determination of (a) latency and (b) per cent supernatant enzyme after sedimentation of zymogen granules. Amylase was used as a zymogen granule marker enzyme. Latency was significantly reduced in pancreatic homogenates of ethanol fed animals suggesting increased zymogen granule fragility. In support of this finding, there was a trend towards increased supernatant enzyme after ethanol feeding. In conclusion, administration of ethanol increases the fragility of pancreatic zymogen granules in the absence of morphological evidence of pancreatic injury. It is proposed that zymogen granule fragility may play an early part in the pathogenesis of alcoholic pancreatitis by permitting contact between digestive and lysosomal enzymes.     

奥曲肽治疗急性坏死性胰腺炎作用机制的实验研究

目的 探讨奥曲肽治疗急性坏死性胰腺炎（ＡＮＰ）的作用机制。方法 作者采用核素示踪和放射自显影技术,研究了奥曲肽对正常大鼠和大鼠ＡＮＰ时胰腺泡细胞氨基酸摄取、酶蛋白合成及分泌功能的影响。结果 奥曲肽对正常胰腺腺泡细胞和呈点同血坏死的ＡＶＰ胰腺腺细胞氨基酸摄取、酶蛋白合成均无明显影响,但可明显抑制胰腺腺胞细胞的外作泌功能,导致细胞内酶原颗粒积聚,ＡＮＰ时胰腺腺泡细胞出现底膜及侧膜异位分泌,奥曲肽能够减     

Daidzin suppresses ethanol consumption by Syrian golden hamsters without blocking acetaldehyde metabolism.

Daidzin is a potent, selective, and reversible inhibitor of human mitochondrial aldehyde dehydrogenase (ALDH) that suppresses free-choice ethanol intake by Syrian golden hamsters. Other ALDH inhibitors, such as disulfiram (Antabuse) and calcium citrate carbimide (Temposil), have also been shown to suppress ethanol intake of laboratory animals and are thought to act by inhibiting the metabolism of acetaldehyde produced from ingested ethanol. To determine whether or not daidzin inhibits acetaldehyde metabolism in vivo, plasma acetaldehyde in daidzin-treated hamsters was measured after the administration of a test dose of ethanol. Daidzin treatment (150 mg/kg per day i.p. for 6 days) significantly suppresses (> 70%) hamster ethanol intake but does not affect overall acetaldehyde metabolism. In contrast, after administration of the same ethanol dose, plasma acetaldehyde concentration in disulfiram-treated hamsters reaches 0.9 mM, 70 times higher than that of the control. In vitro, daidzin suppresses hamster liver mitochondria-catalyzed acetaldehyde oxidation very potently with an IC50 value of 0.4 microM, which is substantially lower than the daidzin concentration (70 microM) found in the liver mitochondria of daidzin-treated hamsters. These results indicate that (i) the action of daidzin differs from that proposed for the classic, broad-acting ALDH inhibitors (e.g., disulfiram), and (ii) the daidzin-sensitive mitochondrial ALDH is not the one and only enzyme that is essential for acetaldehyde metabolism in golden hamsters.     

Small bowel bypass prevents the trophic action of cholecystokinin on the rat pancreas

The effect of a chronic administration of cholecystokinin (CCK) on the rat pancreas has been studied in rats subjected to a 90% jejunoileal bypass or an intestinal transection (controls). Jejunoileal bypass, when compared to transection, did not modify the size of the pancreas but decreased its enzyme content, especially for amylase, and reduced the number of zymogen granules. These structural and biochemical changes were maintained when bypassed animals were treated three times daily and for six days with cholecystokinin (20 Ivy Dog Units (IDU)/kg). In contrast, CCK treatment in transected animals induced growth of the pancreas due to cellular hypertrophy and hyperplasia; pancreatic enzyme content, especially for chymotrypsin, and the population of zymogen granules in acinar cells were also enhanced. It is concluded that jejunoileal bypass prevents the trophic action of chronic CCK on the pancreas.     

Marked differences in immunocytological localization of [3H]estradiol-binding protein in rat pancreatic acinar tumor cells compared to normal acinar cells

[3H]Estradiol can bind to a specific protein in normal rat pancreatic acinar cells. Electron microscopic immunocytochemical analysis has shown this protein to be localized primarily in the rough endoplasmic reticulum and mitochondria. Rat exocrine pancreatic tumor cell lines, whether grown in tissue culture (AR42J) or as a tumor mass after sc injection into rats (DSL-2), lacked detectable amounts of this [3H]estradiol-binding protein (EBP), as determined by the dextran-coated charcoal assay. Furthermore, primary exocrine pancreatic neoplasms induced with the carcinogen azaserine contained little or no detectable [3H]estradiol-binding activity. However, electron immunocytochemical studies of transformed cells indicated the presence of material that cross-reacted with antibodies prepared against the [3H]EBP. The immunopositive reaction in transformed cells was localized almost exclusively in lipid granules. Such lipid organelles in normal acinar cells, although present less frequently than in transformed cells, have never been observed to contain EBP-like immunopositive material. Presumably, the aberrant localization of EBP in these acinar tumor cells results in loss of function of this protein, which in normal pancreatic acinar cells appears to exert a modulating influence on zymogen granule formation and the process of secretion.     

N-乙酰半胱氨酸预防重症急性胰腺炎的实验研究

背景：还原型谷胱甘肽（GSH）是细胞内最重要的非酶类抗氧化剂,各种急性胰腺炎（AP）动物模型均存在腺泡细胞GSH耗竭。目的：探讨N-乙酰半胱氨酸（NAC）对重症急性胰腺炎（SAP）的预防作用及其可能机制。方法：54只健康雄性Wistar大鼠随机分为3组,正常对照组予假手术,AP模型组和NAC预处理组胰胆管逆行注射牛磺胆酸钠以模拟人类SAP,NAC预处理组于造模前30min腹腔注射NAC。分别于术后3h、6h、12h检测血清Ca^2＋、丙二醛（MDA）和胰腺组织GSH,透射电子显微镜（TEM）观察胰腺组织超微结构。结果：术后3h、6h至12h,各组血清Ca^＋浓度、胰腺组织GSH含量逐渐降低,血清MDA水平逐渐升高。NAC预处理组各时点血清Ca^2＋浓度、胰腺组织GSH含量均显著高于AP模型组（P〈0．05）,血清MDA水平显著低于AP模型组（P〈0．05）。TEM观察显示AP模型组腺泡细胞胞质内可见大量空泡,酶原颗粒分泌、排出明显减少;NAC预处理组空泡体积较小,酶原颗粒排出增加。结论：NAC可在SAP早期恢复腺泡细胞的GSH含量,通过抗氧化作用减轻腺泡细胞的氧化损伤,维持细胞内钙平衡,改善酶原颗粒的转运和排泌,从而对SAP的发展产生预防作用。     

Protective effect of 4-hydroxy-TEMPO, a low molecular weight superoxide dismutase mimic, on free radical toxicity in experimental pancreatitis

Summary Rats develop acute pancreatitis when infused iv for 3 h with cerulein (10 μg/kg/h). Autopsies of the pancreas seen by light microscope show interstitial edema, acinar cells vacuolization, and leukocyte margination in pancreatic capillaries; under electron microscope, severe damage concerning mitochondrial and zymogen granules structures are apparent. Particularly, swelling of the mitochondria and disruption of mitochondrial cristae was observed as well as formation of large vacuoles arising from zymogen granules and liposome fusion. A significant increase of lipid hydroperoxide level in the pancreatic tissue was observed. The purpose of this study was to evaluate the effect of 4-hydroxy-TEMPO—a low-mol-wt superoxide dismutase mimic—in a rat cerulein model of acute pancreatitis, with the expectation that free radical mediated hydroperoxide formation and tissue damage may be reduced significantly. Twenty-one male Wistar rats were divided into three groups: Group 1 (n=5) served as a control and was infused iv for 3 h with physiologic saline; Group 2 (n=8) was infused iv for 3 h with cerulein 10 μg/kg/h; and Group 3 (n=8) infused iv both with cerulein and 4-hydroxy-TEMPO 22.6 mg/kg/h. Pancreatic tissue damage was quantified by measuring lipid hydroperoxide (LOOH) level, the weight of the organ, and by light and electron microscopic examination. 4-hydroxy-TEMPO penetration across cellular membrane barriers was quantified by ESR spectrometric measuremts of 4-hydroxy-TEMPO concentration in pancreatic tissue samples and pancreatic juice as well. Administering 4-hydroxy-TEMPO to rats resulted in preventing both lipid hydroperoxide formation and severe morphological damage. 4-hydroxy-TEMPO crossed cellular membrane barriers and was excreted to pancreatic juice. Infusion of 4-hydroxy-TEMPO appears to prevent pancreatic injury caused by free radicals in experimental cerulein pancreatitis.     

Mechanism of octreotide in acute necrotizing pancreatitis (ANP) of rats: An experimental study

OBJECTIVE : To study the action of octreotide in acute necrotizing pancreatitis (ANP) in rats. METHODS : The effect of octreotide on pancreatic acinar cells with respect to amino acid uptake, protein synthesis and secretion of enzymes was observed by using radioactive tracing and autoradiography on both healthy rats and rats with ANP. RESULTS : It was shown that octreotide has no effect on pancreatic acinar cells with respect to amino acid uptake and protein synthesis in both ANP and in control rats. However, octreotide was able to inhibit the secretion of enzyme‐proteins. There were secretions from the basolateral membrane of the acinar cells in ANP rats, which could be reduced by treatment with octreotide. CONCLUSIONS : Octreotide has no effect on pancreatic acinar cells with respect to amino acid uptake and enzyme‐protein synthesis, but it can inhibit the secretion of enzyme‐proteins, in particular, from the basolateral membrane of ANP rats and prevent the accumulation of zymogen granules in the interstitium.     

Alteration of chaperonin60 and pancreatic enzyme in pancreatic acinar cell under pathological condition

AIM: To investigate the changes of chaperonin60 (Cpn60) and pancreatic enzymes in pancreatic acinar cells, and to explore their roles in the development of experimental diabetes and acute pancreatitis (AP). METHODS: Two different pathological models were replicated in Sprague-Dawley rats: streptozotocin-induced diabetes and sodium deoxycholate-induced AP. The contents of Cpn60 and pancreatic enzymes in different compartments of the acinar cells were measured by quantitative immunocytochemistry. RESULTS: The levels of Cpn60 significantly increased in diabetes, but decreased in AP, especially in the zymogen granules of the pancreatic acinar cells. The elevation of Cpn60 was accompanied with the increased levels of pancreatic lipase and chymotrypsinogen in diabetes. However, a decreased Cpn60 level was accompanied by high levels of lipase and chymotrypsinogen in AP. The amylase level was markedly reduced in both the pathological conditions. CONCLUSION: The equilibrium between Cpn60 and pancreatic enzymes in the acinar cells breaks in AP, and Cpn60 content decreases, suggesting an insufficient chaperone capacity. This may promote the aggregation and autoactivation of the premature enzymes in the pancreatic acinar cells and play roles in the development of AP.     

Receptor-mediated endocytosis of [125I]insulin into pancreatic acinar cells in vivo

One of the highest concentrations of insulin receptors is found in the cell membrane of the pancreatic acinar cell. A radioautographic study has been carried out to monitor the fate of in vivo injected 125I-labeled insulin after binding to the acinar cell membrane. [125I]Insulin remained for long periods of time (greater than 45 min) within the exocrine cell. Quantitative radioautography at the electron microscopic level revealed endocytosis of hormone and localization to zymogen granules and, to a lesser extent, multivesicular bodies, lysosomes, structures that were receptosome like, and small undefined structures of about 50-100 nm in diameter found dispersed among endoplasmic reticulum saccules. Treatment with the lysosomotropic agent chloroquine produced large secondary lysosomes which were seldom labeled. Rather, there was an increase in the proportion of label over zymogen granules and receptosome-like structures without increased retention of label by acinar cells. Thus, in pancreatic exocrine cells, nonlysosomal structures are of major quantitative importance in insulin internalization. The high concentration of grains about the bounding membrane of zymogen granules points to a merging of the endocytic and exocytic pathways in pancreatic acinar cells.     

Immunocytochemical localization of pancreatic stone protein in the human digestive tract

Recently, in our laboratory, a protein extracted from human pancreatic stones was characterized and purified and a specific antibody was obtained. This pancreatic stone protein (PSP) was shown to have an inhibitory effect on the CaCO3 crystal growth in vitro. The cellular origin of such a protein and its repartition along the digestive tract were studied by immunolocalization (protein A-colloidal gold method) at the ultrastructural level. Surgical biopsies of pancreata from normal or chronic pancreatitis patients, needle liver biopsies, gastric mucosa, and jejunum and duodenum biopsies were minced and fixed in the Karnovsky medium or in buffered 4% paraformaldehyde. The specimens were washed in buffer, dehydrated through ethanol, and embedded in Epon 812. Ultrathin sections, collected on uncoated nickel grids, were submitted to the following reactives at room temperature: protein A 1 mg/ml, anti-PSP (1:2 to 1:100), and protein A-colloidal gold. The specificity of the localization was checked by substituting buffer or nonimmune rabbit serum to anti-PSP. The stone protein was markedly present in the zymogen granules and condensing vacuoles of the normal pancreatic acinar cells, the label was found in the acinar and ductal lumen. In chronic pancreatitis, the localization of PSP, when it occurred, was extremely weak in the acinar cells. No PSP was specifically characterized in hepatocytes, gastric mucosa, and enterocytes. However, a weak but specific reaction was found in the secretory granules of Paneth cells. These results in pancreas confirm the acinar secretory origin of the PSP and are in good agreement with its possible function in stabilizing pancreatic juice in vivo, which is normally supersaturated in calcium carbonate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Small bowel bypass prevents the trophic action of cholecystokinin on the rat pancreas

Summary The effect of a chronic administration of cholecystokinin (CCK) on the rat pancreas has been studied in rats subjected to a 90% jejunoileal bypass or an intestinal transection (controls). Jejunoileal bypass, when compared to transection, did not modify the size of the pancreas but decreased its enzyme content, especially for amylase, and reduced the number of zymogen granules. These structural and biochemical changes were maintained when bypassed animals were treated three times daily and for six days with cholecystokinin (20 Ivy Dog Units (IDU)/kg). In contrast, CCK treatment in transected animals induced growth of the pancreas due to cellular hypertrophy and hyperplasia; pancreatic enzyme content, especially for chymotrypsin, and the population of zymogen granules in acinar cells were also enhanced. It is concluded that jejunoileal bypass prevents the trophic action of chronic CCK on the pancreas. This work was presented in part at the XVI Meeting of the European Pancreatic Club, Cascais (Portugal), 13–15 September, 1984.     

Steroids and the secretory function of the exocrine pancreas

The influence of steroids on the exocrine pancreas of male rats was examined by removing steroid producing tissue and by introducing individual steroids into these animals at a later date. Castration had no demonstrable morphological effect on acinar cells, whereas castration combined with adrenalectomy caused a marked depletion of zymogen granules as well as widening of peri- and interlobular spaces. Treatment of castrated-adrenalectomized rats with estradiol restored a normal appearance of the pancreas within about 9 h. Triamcinolone acetonide produced similar results. These morphological changes were accompanied by significant alterations of the relative amounts of digestive enzymes present in zymogen granules. A marked reduction of amylase occurred in the castrated-adrenalectomized group. Neither estradiol nor triamcinolone could reverse these effects within 9 h. Castration alone had no significant effect on the relative proportion of amylase; however, it increased the relative amount of proteases. This effect was reversed by estradiol treatment. Estradiol also induced significant changes in the proportion of proelastase in castrated-adrenalectomized animals. Replacement therapy in castrated-adrenalectomized rats with dexamethasone or triamcinolone partially restored the level of amylase in the pancreas, whereas estradiol did not cause any significant effect. At the ultrastructural level, castration and adrenalectomy caused swelling of the Golgi apparatus and accumulation of condensing vacuoles. These effects were reversed by either estradiol or triamcinolone. Also, after acute treatment of these animals with estradiol, two unusual features of acini were noted. In some acini, a type of granule that we termed halo granule appeared. These halo granules were either distinctly separated organelles or formed composite structures that did not appear to be associated with the luminal membrane. Freeze-fracture studies revealed that secretory vesicles in apparently normal acini adhered to each other at specific contact sites characterized by aggregates of intramembrane particles. Multiple sites of contact could be seen in the same vesicle. From our observations it is clear that steroids from the testes and adrenals exert major effects on the secretory apparatus of pancreas; more specifically on the mechanisms that determine the proportions of the different digestive enzyme and on their packaging in the zymogen granules.     

Effect of chronic ethanol consumption on the pancreas of the hamster

The purpose of this study was to determine the effect of chronic ethanol consumption on pancreatic morphology and biochemistry in the hamster, with special attention to lipid changes. A control group of Syrian golden hamsters fed a synthetic liquid diet was compared to an ethanol group pair-fed the same diet with ethanol substituted for 35% of the carbohydrate calories. The animals were sacrificed at 7 weeks and 3, 6, 9, and 12 months. After 12 months of ethanol consumption, a significant decrease in pancreatic triglycerides and a significant increase in pancreatic RNA was seen. These changes were associated with a rise in pancreatic weight and protein content in the ethanol group, reversing a six-month decline in these values. This rise in RNA and protein in the ethanol-treated group corresponded with the appearance of large abnormal zymogen granules. Other ultrastructural features such as lipid droplets, mitochondria, and endoplasmic reticulum were not altered by ethanol. Ethanol did increase the water content of the pancreas. Although ethanol had no effect on the fasting levels of insulin or pancreatic polypeptide, the fasting serum gastrin immunoreactivity was significantly lower in the ethanol animals. This study shows that chronic ethanol consumption produces a metabolic change in the hamster by 12 months which is suggestive of increased protein synthesis with a decrease in pancreatic triglycerides and no lipid droplet formation.This study was supported by the Medical Research Service of the Veterans Administration Medical Center.