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How does Alcohol Kill Cells?

Published online by Cambridge University Press:  01 February 2010

David N. Criddle
Affiliation:
MRC Secretary, Control Research Group, Department of Physiology, School of Biomedical Sciences, Crown Street, University of Liverpool, Liverpool L69 3BX, UK. E-mail: [email protected]

Abstract

Excessive alcohol consumption is linked to a variety of major health problems, including the severe inflammation of the pancreas, which may lead to premature death of the individual.1 Hospital admissions in the United Kingdom due to acute pancreatitis were recently shown to have doubled over a 30 year period,2 in parallel with an estimated doubling of alcohol consumption in this country, and the incidence of the disease is dramatically increasing. Within the European Union, acute pancreatitis may attain an incidence of up to 1 per 1000 individuals per year. In accord with trends in drinking lifestyle in the UK, admissions of younger people and women have correspondingly escalated over the last few decades, and alcohol-related problems have placed a heavy financial burden on the healthcare system. So-called ‘binge drinking’, a prevalent feature of the current ‘drinking culture’, is commonly linked to patients presenting at clinic with episodes of acute pancreatitis, often manifested initially as excruciating abdominal pain and vomiting. Of these individuals, approximately 20% will develop a more extensive form of the disease with significant pancreatic necrosis triggering a systemic inflammatory response syndrome (SIRS) that may cause multiple organ failure; up to a third of these patients will die. The extent of necrotic cell death in these patients is a major determinant of the severity of acute pancreatitis and disease outcome.3 However, the precise way in which alcohol triggers the cellular damage that forms the basis of this severe and debilitating disease has remained elusive.

Type
Focus: Health in Europe
Copyright
Copyright © Academia Europaea 2010

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References

1.Criddle, D. N., McLaughlin, E., Murphy, J. A., Petersen, O. H. and Sutton, R. (2007) The pancreas misled: signals to pancreatitis. Pancreatology, 7, 436446.Google Scholar
2.Goldacre, M. J. and Roberts, S. E. (2004) Hospital admission for acute pancreatitis in an English population, 1963–98: database study of incidence and mortality. British Medical Journal, 328, 14661469.Google Scholar
3.Criddle, D. N., Gerasimenko, J. V., Baumgartner, H. K., Jaffar, M., Voronina, S., Sutton, R., Petersen, O. H. and Gerasimenko, O. V. (2007) Calcium signalling and pancreatic cell death: apoptosis or necrosis? Cell Death and Differentiation, 14, 12851294.CrossRefGoogle ScholarPubMed
4.Pandol, S. J., Saluja, A. K., Imrie, C. W. and Banks, P. A. (2007) Acute pancreatitis: bench to the bedside. Gastroenterology, 133, 1056.CrossRefGoogle Scholar
5.Cawley, T. A. (1788) A singular case of diabetes, consisting entirely in the quantity of urine with an enquiry into the different theories of that disease. London Medical Journal, 9, 286.Google Scholar
6.Friedreich, N. (1878) Disease of the pancreas. In: Ziemssen, H. (ed.) Cyclopoedia of the Practice of Medicine (New York), pp. 549630.Google Scholar
7.Chiari, H. (1896) Über selbstverdauung des menschlichen pancreas. Z. Heilk, 17, 6996.Google Scholar
8.Whitcomb, D. C., Gorry, M. C., Preston, R. A., Furey, W., Sossenheimer, M. J., Ulrich, C. D., Martin, S. P., Gates, L. K. Jr., Amann, S. T., Toskes, P. P., Liddle, R., McGrath, K., Uomo, G., Post, J. C. and Ehrlich, G. D. (1996) Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genetics, 14, 141145.CrossRefGoogle ScholarPubMed
9.Witt, H., Luck, W., Hennies, H. C., Classen, M., Kage, A., Lass, U., Landt, O. and Becker, M. (2000) Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nature Genetics, 25, 213216.CrossRefGoogle ScholarPubMed
10.Nathan, J. D., Romac, J., Peng, R. Y., Peyton, M., Macdonald, R. J. and Liddle, R. A. (2005) Transgenic expression of pancreatic secretory trypsin inhibitor-I ameliorates secretagogue-induced pancreatitis in mice. Gastroenterology, 128, 717727.Google Scholar
11.Apte, M. V., Wilson, J. S., McCaughan, G. W., Korsten, M. A., Haber, P. S., Norton, I. D. and Pirola, R. C. (1995) Ethanol-induced alterations in messenger RNA levels correlate with glandular content of pancreatic enzymes. Journal of Laboratory and Clinical Medicine, 125, 634640.Google Scholar
12.Haber, P. S., Wilson, J. S., Apte, M. V., Korsten, M. A. and Pirola, R. C. (1994) Chronic ethanol consumption increases the fragility of rat pancreatic zymogen granules. Gut, 35, 14741478.Google Scholar
13.Kristiansen, L., Gronbaek, M., Becker, U. and Tolstrup, J. S. (2008) Risk of pancreatitis according to alcohol drinking habits: a population-based cohort study. American Journal of Epidemiology, 168, 932937.CrossRefGoogle ScholarPubMed
14.Pandol, S. J. and Raraty, M. (2007) Pathobiology of alcoholic pancreatitis. Pancreatology, 7, 105114.CrossRefGoogle ScholarPubMed
15.Petersen, O. H., Sutton, R. and Criddle, D. N. (2006) Failure of calcium microdomain generation and pathological consequences. Cell Calcium, 40, 593600.Google Scholar
16.Owyang, C. and Logsdon, C. D. (2004) New insights into neurohormonal regulation of pancreatic secretion. Gastroenterology, 127, 957969.Google Scholar
17.Ji, B., Bi, Y., Simeone, D., Mortensen, R. M. and Logsdon, C. D. (2002) Human pancreatic acinar cells do not respond to cholecystokinin. Pharmacology and Toxicology, 91, 327332.Google Scholar
18.Petersen, O. H. (2005) Ca2+ signalling and Ca2+-activated ion channels in exocrine acinar cells. Cell Calcium, 38, 171200.Google Scholar
19.Murphy, J. A., Criddle, D. N., Sherwood, M., Chvanov, M., Mukherjee, R., McLaughlin, E., Booth, D., Gerasimenko, J. V., Raraty, M. G., Ghaneh, P., Neoptolemos, J. P., Gerasimenko, O. V., Tepikin, A. V., Green, G. M., Reeve, J. R. Jr., Petersen, O. H. and Sutton, R. (2008) Direct activation of cytosolic Ca2+ signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells. Gastroenterology, 135, 632641.Google Scholar
20.Saluja, A., Logsdon, C. and Garg, P. (2008) Direct versus indirect action of cholecystokinin on human pancreatic acinar cells: is it time for a judgment after a century of trial? Gastroenterology, 135, 357360.Google Scholar
21.Petersen, O. H. and Tepikin, A. V. (2008) Polarized calcium signaling in exocrine gland cells. Annual Review of Physiology, 70, 273299.Google Scholar
22.Gerasimenko, J. V., Sherwood, M., Tepikin, A. V., Petersen, O. H. and Gerasimenko, O. V. (2006) NAADP, cADPR and IP3 all release Ca2+ from the endoplasmic reticulum and an acidic store in the secretory granule area. Journal of Cell Science, 119, 226238.Google Scholar
23.Petersen, O. H. (2008) Ca2+-induced pancreatic cell death: roles of the endoplasmic reticulum, zymogen granules, lysosomes and endosomes. Journal of Gastroenterology and Hepatology, 23(Suppl 1), S31S36.CrossRefGoogle ScholarPubMed
24.Ward, J. B., Sutton, R., Jenkins, S. A. and Petersen, O. H. (1996) Progressive disruption of acinar cell calcium signaling is an early feature of cerulein-induced pancreatitis in mice. Gastroenterology, 111, 481491.CrossRefGoogle ScholarPubMed
25.Sutton, R., Criddle, D., Raraty, M. G., Tepikin, A., Neoptolemos, J. P. and Petersen, O. H. (2003) Signal transduction, calcium and acute pancreatitis. Pancreatology, 3, 497505.Google Scholar
26.Raraty, M., Ward, J., Erdemli, G., Vaillant, C., Neoptolemos, J. P., Sutton, R. and Petersen, O. H. (2000) Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells. Proceedings of the National Academy of Sciences, USA, 97, 1312613131.Google Scholar
27.Voronina, S., Longbottom, R., Sutton, R., Petersen, O. H. and Tepikin, A. (2002) Bile acids induce calcium signals in mouse pancreatic acinar cells: implications for bile-induced pancreatic pathology. Journal of Physiology, 540, 4955.Google Scholar
28.Kim, J. Y., Kim, K. H., Lee, J. A., Namkung, W., Sun, A. Q., Ananthanarayanan, M., Suchy, F. J., Shin, D. M., Muallem, S. and Lee, M. G. (2002) Transporter-mediated bile acid uptake causes Ca2+-dependent cell death in rat pancreatic acinar cells. Gastroenterology, 122, 19411953.Google Scholar
29.Criddle, D. N., Raraty, M. G., Neoptolemos, J. P., Tepikin, A. V., Petersen, O. H. and Sutton, R. (2004) Ethanol toxicity in pancreatic acinar cells: mediation by nonoxidative fatty acid metabolites. Proceedings of the National Academy of Sciences, USA, 101, 1073810743.Google Scholar
30.Kono, H., Nakagami, M., Rusyn, I., Connor, H. D., Stefanovic, B., Brenner, D. A., Mason, R. P., Arteel, G. E. and Thurman, R. G. (2001) Development of an animal model of chronic alcohol-induced pancreatitis in the rat. American Journal of Physiology, Gastrointestinal and Liver Physiology, 280, G1178G1186.Google Scholar
31.Pfutzer, R. H., Tadic, S. D., Li, H. S., Thompson, B. S., Zhang, J. Y., Ford, M. E., Eagon, P. K. and Whitcomb, D. C. (2002) Pancreatic cholesterol esterase, ES-10, and fatty acid ethyl ester synthase III gene expression are increased in the pancreas and liver but not in the brain or heart with long-term ethanol feeding in rats. Pancreas, 25, 101106.Google Scholar
32.Miyasaka, K., Ohta, M., Takano, S., Hayashi, H., Higuchi, S., Maruyama, K., Tando, Y., Nakamura, T., Takata, Y. and Funakoshi, A. (2005) Carboxylester lipase gene polymorphism as a risk of alcohol-induced pancreatitis. Pancreas, 30, e87e91.Google Scholar
33.Laposata, E. A. and Lange, L. G. (1986) Presence of nonoxidative ethanol metabolism in human organs commonly damaged by ethanol abuse. Science, 231, 497499.Google Scholar
34.Diczfalusy, M. A., Bjorkhem, I., Einarsson, C., Hillebrant, C. G. and Alexson, S. E. (2001) Characterization of enzymes involved in formation of ethyl esters of long-chain fatty acids in humans. Journal of Lipid Research, 42, 10251032.Google Scholar
35.Werner, J., Laposata, M., Fernandez-del Castillo, C., Saghir, M., Iozzo, R. V., Lewandrowski, K. B. and Warshaw, A. L. (1997) Pancreatic injury in rats induced by fatty acid ethyl ester, a nonoxidative metabolite of alcohol. Gastroenterology, 113, 286294.CrossRefGoogle Scholar
36.Best, C. A. and Laposata, M. (2003) Fatty acid ethyl esters: toxic non-oxidative metabolites of ethanol and markers of ethanol intake. Frontiers of Bioscience, 8, e202e217.Google Scholar
37.Werner, J., Saghir, M., Warshaw, A. L., Lewandrowski, K. B., Laposata, M., Iozzo, R. V., Carter, E. A., Schatz, R. J. and Fernandez-del Castillo, C. (2002) Alcoholic pancreatitis in rats: injury from nonoxidative metabolites of ethanol. American Journal of Physiology, Gastrointestinal and Liver Physiology, 283, G65G73.CrossRefGoogle ScholarPubMed
38.Criddle, D. N., Murphy, J., Fistetto, G., Barrow, S., Tepikin, A. V., Neoptolemos, J. P., Sutton, R. and Petersen, O. H. (2006) Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis. Gastroenterology, 130, 781793.Google Scholar
39.Lange, L. G. and Sobel, B. E. (1983) Mitochondrial dysfunction induced by fatty acid ethyl esters, myocardial metabolites of ethanol. Journal of Clinical Investigation, 72, 724731.CrossRefGoogle ScholarPubMed
40.Criddle, D. N.. Unpublished data.Google Scholar
41.Criddle, D. N., Sutton, R. and Petersen, O. H. (2006) Role of Ca in pancreatic cell death induced by alcohol metabolites. Journal of Gastroenterology and Hepatology, 21(Suppl 3), S14S17.Google Scholar
42.Morton, C., Klatsky, A. L. and Udaltsova, N. (2004) Smoking, coffee, and pancreatitis. American Journal of Gastroenterology, 99, 731738.CrossRefGoogle ScholarPubMed
43.Mukherjee, R., Criddle, D. N., Gukvoskaya, A., Pandol, S., Petersen, O. H. and Sutton, R. (2008) Mitochondrial injury in pancreatitis. Cell Calcium, 44, 1423.Google Scholar