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Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756
2To whom correspondence should be addressed. E-mail: daniel.s.longnecker{at}dartmouth.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPANCREATIC GROWTH AND...EXOCRINE FUNCTIONTOXICITY AND EXPERIMENTALLY...FOLATE-MEDIATED PATHWAYS IN THE...CARCINOGENESIS IN THE PANCREASDIABETESRECOMMENDATIONSLITERATURE CITED |
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KEY WORDS: • hypomethylation • choline deficiency • pancreatitis • pancreatic carcinogenesis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPANCREATIC GROWTH AND...EXOCRINE FUNCTIONTOXICITY AND EXPERIMENTALLY...FOLATE-MEDIATED PATHWAYS IN THE...CARCINOGENESIS IN THE PANCREASDIABETESRECOMMENDATIONSLITERATURE CITED |
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); however, studies in a variety of experimental systems document that the pancreas is affected by dietary deficiency of both methyl donors and folate. Disturbed methylation is implicated in abnormalities of growth, differentiation and function of the exocrine pancreas as well as its response to toxins and carcinogens. The experimental data that support this conclusion are reviewed below. The endocrine cells of the pancreas (islets) seem to be less affected than the acinar tissue by methyl deficiency; however, recent data support the idea that severe diabetes can contribute to the development of a hypomethylating environment that might contribute to the pathogenesis of diabetic complications. |
PANCREATIC GROWTH AND DIFFERENTIATION |
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TOPABSTRACTINTRODUCTIONPANCREATIC GROWTH AND...EXOCRINE FUNCTIONTOXICITY AND EXPERIMENTALLY...FOLATE-MEDIATED PATHWAYS IN THE...CARCINOGENESIS IN THE PANCREASDIABETESRECOMMENDATIONSLITERATURE CITED |
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,3
). The experimental system involved organ culture of pancreas harvested at gestation d 13. The pancreatic anlage was maintained in semidefined or chemically defined medium for periods of 9–12 d in various experiments. Pancreatic growth and differentiation were evaluated by histology, electron microscopy and assay of exocrine enzyme activity. Pancreatic growth and development and the development of rough endoplasmic reticulum and zymogen granules were assessed morphologically. Morphologic indices of acinar cell differentiation showed a general correlation with biochemical assays of the activity of amylase, lipase and chymotrypsin. Data in Table 1
indicate that there is a basal requirement for methionine for growth of the exocrine pancreas, and that higher levels are required to achieve partial or full differentiation of acinar cells. The basal requirement was determined to be 30 mg/L methionine, and a level of 80 mg/L supported maximal differentiation. Electron microscopy showed abundant rough endoplasmic reticulum (RER) and mature zymogen granules in the presence of 80 mg/L methionine, whereas RER was diminished, zymogen granules were absent and nucleoli were greatly enlarged at the level of 30 mg/L. The addition on d 1–9 of either methionine or S-adenosylmethionine (SAM)3
to pancreas cultured with the basal level of methionine yielded a prompt increase in enzyme activity to nearly control levels (2
). SAM was more effective on a molar basis than methionine in this experiment. The requirement for methyl groups could be partially met by choline supplementation (150 mg/L) in the presence of the basal level of methionine, but this high level of choline failed to overcome completely the methionine requirement. A supplement of homocysteine enhanced the effectiveness of the choline supplement in the presence of the basal level of methionine, suggesting that this enhanced the formation of SAM (3
).
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). Such foci have been observed after a variety of experimental manipulations in rats and hamsters, including carcinogen treatment, feeding of copper-deficient diets, administration of peroxisome-proliferating agents and feeding methyl-deficient diets. A low incidence of hepatocytic foci in the pancreas was noted in hamsters fed a methionine-deficient diet and given daily ethionine injections for 8 d, although a higher incidence was observed with the addition of carcinogen treatment. No such foci were seen in a second control group fed a methionine-sufficient diet without ethionine and with carcinogen treatment (5
). A similar observation was reported in rats fed a severely methyl group-deficient diet (6
). |
EXOCRINE FUNCTION |
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TOPABSTRACTINTRODUCTIONPANCREATIC GROWTH AND...EXOCRINE FUNCTIONTOXICITY AND EXPERIMENTALLY...FOLATE-MEDIATED PATHWAYS IN THE...CARCINOGENESIS IN THE PANCREASDIABETESRECOMMENDATIONSLITERATURE CITED |
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,3
) suggested that methyl deficiency would affect pancreatic function, this issue has been addressed more directly in studies demonstrating that ethionine pretreatment inhibits amylase secretion from freshly isolated acini (7
). The same investigators demonstrated that several inhibitors of methylation inhibit amylase secretion by AR42J cells (derived from a rat acinar cell carcinoma) in vitro. Others have reported that diets containing 0.5% ethionine to mice caused a marked reduction in the rate of protein and amylase discharge from the pancreas and that this effect was enhanced by feeding a choline-deficient diet (8
). |
TOXICITY AND EXPERIMENTALLY INDUCED PANCREATITIS |
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TOPABSTRACTINTRODUCTIONPANCREATIC GROWTH AND...EXOCRINE FUNCTIONTOXICITY AND EXPERIMENTALLY...FOLATE-MEDIATED PATHWAYS IN THE...CARCINOGENESIS IN THE PANCREASDIABETESRECOMMENDATIONSLITERATURE CITED |
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) and was studied as a model of pancreatitis by several investigators (10
). Similar changes are reported in several species. The formation of stable levels of S-adenosylethionine (SAE) was reported in one study that ruled out induction of ATP deficiency and incorporation of ethionine into protein as probable mechanisms (11
). SAE is a good inhibitor of transmethylation reactions (12
).
In 1975 Lombardi (13
) reported the induction of acute hemorrhagic pancreatitis with 100% mortality in young female mice fed a choline-deficient diet containing 0.5% ethionine. This diet-induced model of acute pancreatitis is attributed to abnormalities of membrane structure, reflecting hypomethylation of phospholipids (13
) or proteins (14
). Abnormalities of membrane structure and function seem to destroy intracellular compartmentation and to allow the intracellular activation of destructive hydrolytic pancreatic exocrine enzymes. The synergism between choline deficiency and ethionine treatment in the formation of acute hemorrhagic pancreatitis is seen in the fact that feeding 0.5% ethionine in a choline-sufficient purified diet or in a chow diet lowered the mortality to 10% in young female mice, while feeding the choline-deficient diet without ethionine yielded neither mortality nor pancreatitis (13
).
Although there is no direct counterpart for the ethionine model in humans, several drugs are associated with the occurrence of acute pancreatitis (15
). This list includes didanosine, 6-mercaptopurine, sulfonamides and valproic acid. Some of these may deplete the pools of methyl donors and thereby predispose to the development of pancreatitis. The incidence of pancreatitis among patients who receive these drugs is sporadic and is regarded as an anomaly. Such an idiosyncratic response could be a manifestation of genetic polymorphisms that affect methyl metabolism, leaving some patients more vulnerable than others.
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FOLATE-MEDIATED PATHWAYS IN THE PANCREAS |
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TOPABSTRACTINTRODUCTIONPANCREATIC GROWTH AND...EXOCRINE FUNCTIONTOXICITY AND EXPERIMENTALLY...FOLATE-MEDIATED PATHWAYS IN THE...CARCINOGENESIS IN THE PANCREASDIABETESRECOMMENDATIONSLITERATURE CITED |
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). Glycine N-methyltransferase (EC 2.1.1.20), which requires folate coenzymes, is abundant in the liver and pancreas of rats (17
,18
). The ratio of SAM to S-adenosylhomocysteine (SAH) is significantly reduced in rats fed a folate-deficient diet (19
). The pancreas of rats fed a folate-deficient diet contained more immature secretory granules than the pancreas of controls (16
), and pancreatic amylase secretion was reduced in folate-deficient rats (20
). In the context of the studies of Parsa et al. (2
,3
), these studies suggest that pancreatic exocrine function was reduced as a result of disturbed methyl metabolism secondary to dietary folate deficiency. |
CARCINOGENESIS IN THE PANCREAS |
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TOPABSTRACTINTRODUCTIONPANCREATIC GROWTH AND...EXOCRINE FUNCTIONTOXICITY AND EXPERIMENTALLY...FOLATE-MEDIATED PATHWAYS IN THE...CARCINOGENESIS IN THE PANCREASDIABETESRECOMMENDATIONSLITERATURE CITED |
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,22
). This regimen is reported to yield intraductal or invasive carcinomas in 84% of hamsters autopsied at 70 d (21
). Interim autopsies have shown the presence of intraductal hyperplasia in hamsters autopsied at 32 d after two cycles of augmentation, and atypical intraductal hyperplasia as early as 46 d following three cycles (23
).
In rats, most chemical carcinogens examined have induced acinar cell carcinomas. The effects of a choline-deficient diet on carcinogenesis in azaserine-treated rats have yielded variable results. An increased incidence of neoplasms in the choline-deficient group in one experiment was thought to reflect the high fat content (20%) of the experimental diet compared with the control diet (5%) (24
). A second group reported that the incidence of azaserine-induced focal hyperplasia in rat experiments of 4 and 6 mo duration was lower in a choline-deficient diet than in the control choline-sufficient group in a study in which both diets contained the same levels of fat (14%) (25
). A third group reported an increased incidence of azaserine-induced focal hyperplasia in rats fed a choline-deficient diet compared with a group fed a choline-sufficient diet in a short term study (26
). Both diets contained a high level of fat (30%). In a study of rats fed choline-deficient or choline-sufficient high fat diets, the incidence of spontaneously occurring acinar cell neoplasms was similar in the two groups (27
). Thus, it is not clear that methyl deficiency in the absence of a high fat diet has an effect on the development of acinar cell carcinomas in rats.
One relevant epidemiologic study reports an inverse relationship of risk for carcinoma of the pancreas and serum folate levels among a group of male smokers with a significant P-value for trend (28
). Thus, the observations in the hamster model and this study in humans provide support for an enhanced risk of pancreatic carcinoma among populations with a hypomethylation state.
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DIABETES |
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TOPABSTRACTINTRODUCTIONPANCREATIC GROWTH AND...EXOCRINE FUNCTIONTOXICITY AND EXPERIMENTALLY...FOLATE-MEDIATED PATHWAYS IN THE...CARCINOGENESIS IN THE PANCREASDIABETESRECOMMENDATIONSLITERATURE CITED |
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). It is not clear whether these changes are due to metabolic changes specifically associated with diabetes or rather those associated with renal failure. |
RECOMMENDATIONS |
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TOPABSTRACTINTRODUCTIONPANCREATIC GROWTH AND...EXOCRINE FUNCTIONTOXICITY AND EXPERIMENTALLY...FOLATE-MEDIATED PATHWAYS IN THE...CARCINOGENESIS IN THE PANCREASDIABETESRECOMMENDATIONSLITERATURE CITED |
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If human populations are at risk for a nutritionally or drug-induced hypomethylation state, such groups should be evaluated to see whether they are at increased risk for pancreatic insufficiency, pancreatitis or pancreatic cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BOP, N-nitrosobis(2-oxopropyl)amine; MTHFR, methyltetrahydrofolate reductase; RER, rough endoplasmic reticulum; SAE, S-adenosylethionine; SAH, S-adenylsylhomocysteine; SAM, S-adenosylmethionine.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONPANCREATIC GROWTH AND...EXOCRINE FUNCTIONTOXICITY AND EXPERIMENTALLY...FOLATE-MEDIATED PATHWAYS IN THE...CARCINOGENESIS IN THE PANCREASDIABETESRECOMMENDATIONSLITERATURE CITED |
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1. Longnecker, D. (1985) Nutritionally induced pancreatic disease. Sidransky, H. eds. Nutritional Pathology 1985:115-126 Marcel Dekker New York, NY. .
2. Parsa, I., Marsh, W. & Fitzgerald, P. (1970) Pancreas acinar cell differentiation. 3. Importance of methionine in differentiation of pancreas anlage in organ culture. Am. J. Pathol. 59:1-22.[Medline]
3. Parsa, I., Marsh, W. & Fitzgerald, P. (1972) Pancreas acinar cell differentiation. VI. Effects of methyl donors and homocysteine. Fed. Proc. 31:166-175.[Medline]
4. Rao, M., Dwivedi, R., Subbarao, V., Usman, M., Scarpelli, D., Nemali, M., Yeldandi, A., Thangada, S., Kumar, S. & Reddy, J. (1988) Almost total conversion of pancreas to liver in the adult rat: a reliable model to study transdifferentiation. Biochem. Biophys. Res. Commun. 156:131-136.[Medline]
5. Scarpelli, D. & Rao, M. (1981) Differentiation of regenerating pancreatic cells into hepatocyte-like cells. Proc. Natl. Acad. Sci. USA 78:2577-2581.
6. Hoover, K. & Poirier, L. (1986) Hepatocyte-like cells within the pancreas of rats fed methyl-deficient diets. J. Nutr. 116:1569-1575.
7. Capdevila, A., Decha-Umphai, W., Song, K., Borchardt, R. & Wagner, C. (1997) Pancreatic exocrine secretion is blocked by inhibitors of methylation. Arch. Biochem. Biophys. 345:47-55.[Medline]
8. Gilliland, L. & Steer, M. (1980) Effects of ethionine on digestive enzyme synthesis and discharge by mouse pancreas. Am. J. Physiol. 239:G418-G426.
9. Farber, E. & Popper, H. (1950) Production of acute pancreatitis with ethionine and its prevention by methionine. Proc. Soc. Exp. Biol. Med. 74:838-840.
10. Niederau, C., Luthen, R., Niederau, M., Grendell, J. & Ferrell, L. (1992) Acute experimental hemorrhagic-necrotizing pancreatitis induced by feeding a choline-deficient, ethionine-supplemented diet: methodology and standards. Eur. Surg. Res. 24(Suppl.):40-54.
11. Longnecker, D., Farber, E. & Shull, H. (1968) The biochemical pathology of ethionine-induced pancreatic damage: incorporation of ethionine into protein and ATP levels in pancreas of rats. Arch. Biochem. Biophys. 127:601-612.[Medline]
12. Alix, J.H. (1982) Molecular aspects of the in vivo and in vitro effects of ethionine, an analog of methionine. Microbiol. Rev. 46:281-295.
13. Lombardi, B. (1976) Influence of dietary factors on the pancreatotoxicity of ethionine. Am. J. Pathol. 84:633-648.[Abstract]
14. Gilliland, E., Turner, N. & Steer, M. (1981) The effects of ethionine administration and choline deficiency on protein carboxymethylase activity in mouse pancreas. Biochim. Biophys. Acta 672:280-287.[Medline]
15. Longnecker, D. S. & Wilson, G. L. (1991) Pancreas. Haschek-Hock, W. M. Rousseaux, C. G. eds. Handbook of Toxicologic Pathology 1991:253-278 Academic Press San Diego, CA. .
16. Balaghi, M., Horne, D., Woodward, S. & Wagner, C. (1993) Pancreatic one-carbon metabolism in early folate deficiency in rats. Am. J. Clin. Nutr. 58:198-203.
17. Yeo, E. & Wagner, C. (1992) Purification and properties of pancreatic glycine N-methyltransferase. J. Biol. Chem. 267:24669-24674.
18. Yeo, E. & Wagner, C. (1994) Tissue distribution of glycine N-methyltransferase, a major folate-binding protein of liver. Proc. Natl. Acad. Sci. USA 91:210-214.
19. Balaghi, M. & Wagner, C. (1992) Methyl group metabolism in the pancreas of folate-deficient rats. J. Nutr. 122:1391-1396.
20. Balaghi, M. & Wagner, C. (1995) Folate deficiency inhibits pancreatic amylase secretion in rats. Am. J. Clin. Nutr. 61:90-96.
21. Mizumoto, K., Tsutsumi, M., Denda, A. & Konishi, Y. (1988) Rapid production of pancreatic carcinoma by initiation with N-nitroso-bis(2-oxopropyl)amine and repeated augmentation pressure in hamsters. J. Natl. Cancer Inst. 80:1564-1567.
22. Mizumoto, K., Tsutsumi, M., Kitazawa, D., Denda, A. & Konishi, Y. (1990) Usefulness of rapid production model for pancreatic carcinoma in male hamsters. Cancer Lett 49:211-215.[Medline]
23. Tsutsumi, M., Kondoh, S., Noguchi, O., Horiguchi, K., Kobayashi, E., Okita, S., Ohashi, K., Honoki, K., Tsujiuchi, T. & Konishi, Y. (1993) K-ras gene mutation in early ductal lesions induced in a rapid production model for pancreatic carcinomas in Syrian hamsters. Jpn. J. Cancer Res. 84:1101-1105.[Medline]
24. Roebuck, B., Yager, J. J. & Longnecker, D. (1981) Dietary modulation of azaserine-induced pancreatic carcinogenesis in the rat. Cancer Res. 41:888-893.
25. Shinozuka, H., Katyal, S. & Lombardi, B. (1978) Azaserine carcinogenesis: organ susceptibility change in rats fed a diet devoid of choline. Int. J. Cancer 22:36-39.[Medline]
26. Andry, C., Kupchik, H. & Rogers, A. (1990) L-Azaserine induced preneoplasia in the rat pancreas: a morphometric study of dietary manipulation (lipotrope deficiency) and ultrastructural differentiation. Toxicol. Pathol. 18:10-17.[Medline]
27. Longnecker, D. S., Chandar, N., Sheahan, D. G., Janosky, J. E. & Lombardi, B. (1991) Preneoplastic and neoplastic lesions in the pancreas of rats fed choline-devoid or choline-supplemented diets. Toxicol. Pathol. 19:59-65.[Medline]
28. Stolzenberg-Solomon, R., Albanes, D., Nieto, F., Hartman, T., Tangrea, J., Rautalahti, M., Sehlub, J., Virtamo, J. & Taylor, P. (1999) Pancreatic cancer risk and nutrition-related methyl-group availability indicators in male smokers. J. Natl. Cancer Inst. 91:535-541.
29. Poirier, L. A., Brown, A. T., Fink, L. M., Wise, C. K., Randolph, C. J., Delongchamp, R. R. & Fonseca, V. A. (2001) Blood S-adenosylmethionine concentrations and lymphocyte methylenetetrahydrofolate reductase activity in diabetes mellitus and diabetic nephropathy. Metabolism 50:1014-1018.[Medline]
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