There are some toxic agents that cause damage to the exocrine pancreas resulting in acute or chronic pancreatitis or cancer.44 The toxic agents include toxic chemicals (see Chapter 22), therapeutic drugs, hormones, and bile salts. Chemicals toxic to the pancreas included alcohol (see Chapter 15), alloxan, streptozotocin, azaserine, dimethylbenzo[a]anthracene, ethio-nine, methanol, oleic acid, 4-hydroxyaminoquinoline-1-oxide, beta-oxidized derivatives of dipropylnitrosamine, and chloroform that can cause acute pancreatic injury and death or hyperplasia, metaplasia, and malignant transformation. Toxic therapeutic agents that are known to induce acute pancreatitis include azathioprine, estrogens, furosemide, methyldopa, pen-tamidineprocainamide, sulfonamides, and thiazide diuretics. The immuno-suppressants FK506 and cyclosporine A also inhibit pancreatic secretory response to CCK and cause tissue damage in the exocrine pancreas. CCK and its analog cerulein are also toxic to the exocrine pancreas when administered in high dose leading to acute pancreatitis (see Chapter 14). Injection of a bile salt in high dose to the pancreatic duct also caused acute pancreatitis. A similar condition may arise if the common bile duct is obstructed due to tumor growth or blockage by a gallstone.
The mechanism of pancreatic tissue injury may vary with the toxic agents. The effect of ethanol, however, is studied most extensively (see Chapter 15). The cause of pancreatic damage by alcohol may be due to premature activation of digestive enzyme in the acinar cells. It has been shown that alcohol increases the synthesis of digestive enzyme in the pancreas45 and increases the fragility of the zymogen granules46 and lysosomes.47 Premature activation of pancreatic protease by lysosomal cathepsin B may lead to the subsequent tissue damage. Long-term consumption of alcohol increases gene expression of pancreatic cholesterol esterase, ES-10 and fatty acid ethyl ester synthase III in rats48 that may be the cause of accumulation of cholesteryl esters and fatty acid ethyl esters (FAEEs), ethanol metabolites that increase the fragility of the lysosomes, in the pancreas.47,49 On the other hand, the fragility of zymogen granules is increased by alcohol through reduced synthesis of the granule membrane protein, GP2. Alcohol also increases production of reactive oxygen species or free radicals. It has been shown that acute alcohol consumption increases the level of lipid peroxidation products in rat pancreas, resulting from reaction of oxygen free radicals with the membrane components. Formation of alcohol toxic metabolites such as acetaldehyde and FAEEs in the pancreas can also increase tissue injury.
Intravenous infusion of ethanol at low dose significantly increased PES in dogs, whereas infusion of ethanol at high dose inhibited PES. The alcohol-stimulated pancreatic protein secretion in the rat appeared to be mediated through the release of a CCK-RP,50 whereas the increased fluid and bicarbonate secretion was not mediated through the release of secre-tin. The effects of acute ethanol were abolished by atropine indicating involvement of a cholinergic component. Indeed it was reported that in alcoholic dogs, pancreatic protein secretion became resistant to bethanechol.51 It was observed in mice that after prolonged (4 months) alcohol consumption, the majority of periacinar nerve terminal exhibited degenerative changes and there were slight decreases in the intensity of VIP and SP immomunoreactivity and near abolishment of PP-containing fibers.52 The observation also suggested changes in neural regulation. In long-term alcohol-fed dogs, postprandial PES decreased as compared with nonalcoholic dogs. However, secretagogue-stimulated PES after long-term alcohol consumption may vary depending on the extent of tissue damage. The effect of other toxic agents may involve some similar mechanisms of tissue injury. On the other hand, drugs such as alloxan, streptozotocin, and cyclosporine that also affect the endocrine pancreas may also reduce secretin- and CCK-stimulated PES by abolishing insulin secretion (see Chapter 27). Endogenous CCK appears to increase the extent of tissue injury exerted by a toxic agent, as administration of a CCK receptor antagonist often lessens the injury. In addition, drugs abused together often caused more profound pancreatic tissue damage. The best examples are alcohol consumption-cigarette smoking and alcohol-cocaine abuse. It has been reported that cigarette smoke enhanced ethanol-induced pancreatic tissue damage in rats.53 Nicotine appears to be one of the toxic agents in cigarette smoking as it is known to cause pancreatic tissue damage and inhibits CCK-stimulated amylase secretion from isolated rat pancreatic acini.54 Cocaine inhibited CCK- and urecholine-stimulated amy-lase secretion and inhibited protein synthesis in isolated rat pancreatic tissue.55 The inhibition of protein synthesis by cocaine was also observed in vivo. Combination of cocaine with ethanol resulted in a greater extent of inhibition of carbachol- and cerulein-stimulated amylase secretion from isolated guinea pig pancreatic lobules than that exerted by each drug alone. The metabolite of cocaine and ethanol, cocaethylene exhibited a more potent inhibitory effect on amylase secretion than its parent compounds combined.56 Because cocaethylene is formed in vivo when cocaine and alcohol are abused together, it may contribute to pancreatic tissue damage caused by coadministration of the two drugs. Nevertheless, regardless of the mechanism of tissue injury, once pancreatitis is developed, there is a diminished secretory response to secretin and CCK.
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