Toxic Effects on Pancreas



The pancreas is an annex organ of digestive system, rich blood supplied, with endocrine and exocrine functions. The xenobiotics can damage both of its functions. Streptozocin and alloxan are the most known agents that affect endocrine function. The principal mechanisms for toxic damage of exocrine function consist of: perturbation of zymogen granule trafficking, oxidant stress, localized ischemia, pancreatic ductal stenosis or occlusion, immune-mediated disease, exposure to carcinogens.

Pancreatitis is the most common clinical manifestation of pancreatic toxic aggression produced by various xenobiotics. Are known over 120 xenobiotics (drugs, substance abuse and other chemical agents) responsible for pancreatic damage through: pancreatic duct constriction, cytotoxic and metabolic effects, accumulation of a toxic metabolite or intermediary, hypersensitivity reactions, hypertriglyceridemia, chronic hypercalcemia, localized angioedema effect in the pancreas, arteriolar thrombosis. Statins, diuretics, heart therapy, oral contraceptives, valproic acid, antiviral therapy are presented in the literature as being responsible for pancreatic toxicity. The ethanol, in chronic consumption, produces frequently acute pancreatitis, through different mechanisms. Other agents responsible for toxic effects on pancreas are nicotine, cocaine, pesticides, metals etc.


Table of Contents:

1. Introduction

2. Toxic Effects on Endocrine Function

3. Toxic Effects on Exocrine Function

4. Conclusions


1. Introduction

The pancreas is an annex organ of digestive system, rich blood supplied, with endocrine and exocrine functions. Approximately 80% of the gross weight of the pancreas supports exocrine function, and 20% is involved with endocrine function. [1] While the endocrine pancreas secretes insulin, a hormone needed to control the body’s glucose, the exocrine pancreas synthesizes and stores zymogens (inactive forms of digestive enzymes such as trypsinogen) required for the digestion of food. [2] The pancreas secretes 1500-3000 mL of iso-osmotic alkaline (pH>8.0) fluid per day containing many enzymes and zymogens. [1] Although it is not a common target organ, the xenobiotics can damage both of its functions. [3]


2. Toxic Effects on Endocrine Function

Streptozocin and alloxan produce destruction of pancreatic beta cells (responsible with insulin synthesis) with hyperglycemia. [4] Alloxan toxicity may be mediated through generation of reactive oxygen containing radicals. Also, alloxan can produce hyperplasia of pancreatic islets. [5] Cyclosporine and tacrolimus can cause abnormalities in glucose metabolism, explained by cytoplasmic swelling, vacuolization, apoptosis, and abnormal immunostaining for insulin. [4] Corticosteroids, growth hormone or glucagon are, also, responsible for hyperplasia of islets. Beside streptozocin and alloxan, other xenobiotics are inducers for pancreatic islet cell tumors (neoplasia) in rats: pyrrolizidine alkaloids, sulpiride, medroxyprogesterone acetate, nafarelin acetate. [5]


3. Toxic Effects on Exocrine Function

The principal mechanisms for toxic damage of pancreatic exocrine function consist of: perturbation of zymogen granule trafficking, degranulation (loss of zymogen granules), accumulation of a toxic metabolite or intermediary, oxidant stress, cytotoxic and metabolic effects, pancreatic ductal stenosis or occlusion, angioedema effect, arteriolar thrombosis, hypertriglyceridemia, chronic hypercalcemia, hypersensitivity reactions, exposure to carcinogens. [3], [6], [7]

The consequences of these mechanisms are: atrophy (degeneration) or hyperplasia (hypertrophy) of cells, membrane breakdown, interstitial cell vacuolization, enzymatic digestion, fatty change, localized ischemia, localized acidosis, necrosis, apoptosis, inflammation, fibrosis, immune-mediated diseases, neoplasia. [3], [7]

Pancreatitis is the most common clinical manifestation of pancreatic toxic aggression produced by various xenobiotics. Are known over 120 xenobiotics, drugs, substance abuse and other chemical agents, responsible for acute pancreatitis (AP). [6] Any factor (eg, drugs or alcohol) that causes an abrupt increase in serum triglycerides to levels >1000 mg/dL can precipitate a bout of pancreatitis that can even become fulminant. [1]

In patients younger than 55 years, low levels of uridine 5-diphosphate glucuronosyltransferase UGT1A7*3, which is found in the pancreas, have been associated with an increased risk of pancreas cancer. [8]



Drugs of all types are related to the etiology of pancreatitis in approximately 1.4-2.0% of cases. [9] More than 100 drugs have been implicated in causing AP. [10] Published case reports of drug- induced AP exist for at least 40 drugs of the top 200 most prescribed medications. [11].

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme inhibitors decrease the degradation of bradykinin. The releasing of bradykinin is in concordance with increased vascular permeability in the pancreas, with local angioedema of the pancreatic duct, during AP. [6] The higher risk of AP occured within the first 6 months of initiating therapy. Lastly, angiotensin II receptors may be important in the regulation of pancreatic secretion and microcirculation. [11]


The mechanism of the AP produced by statins may be related to a direct toxic effect to the pancreas and the accumulation of a toxic metabolite, also to rhabdomyolysis, myalgia, and/or metabolism or drug interactions through cytochrome P-450 3A4 (CYP3A4). [6], [11], [12]

Pravastatin may have fewer case reports of drug-induced AP than other statins because it is not metabolized by CYP3A4. [11]

Oral Contraceptives/Hormone Replacement Therapy

Oral contraceptives and hormone replacement therapy, with estrogen with or without progestins, produce AP through hypertriglyceridemia and a hypercoagulable state with pancreatic necrosis. [6]


Furosemide induces AP through direct toxic effect to the pancreas (including degranulation), diuretic-induced stimulation of pancreatic secretion, and ischemia. [7], [11] Hydrochlorothiazides increase the risk for AP through hypercalcemia (hydrochlorothiazides increase calcium resorption from bone with increased levels of serum calcium, and can produce also hyperparathyroidism) and hyperlipidemia. [6]

Highly Active Antiretroviral Therapy

Patients infected with HIV are 35 to 800 times more likely to develop AP than the general population. [6], [11] Protease inhibitors (PIs) can cause metabolic disturbances, including development of insulin resistance, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia. [6]

Didanosine is clearly associated with pancreatitis. [3], [13]

Valproic Acid

Valproic acid-induced AP has been reported since 1979 and is noted to occur more often in children (13% estimated incidence). [11] Valproic acid could induce AP through direct toxic effect of free radicals on the pancreatic tissue and depletion of superoxide dismutase, catalase, and glutathione peroxidase. [6] Valproic acid-induced AP typically occurs within the first year of treatment. [11] This risk increases in patients with a history of drug sensitivity. [6]

Hypoglycemic Agents

Various oral hypoglycemic agents (biguanide agents, dipeptidyl peptidase 4 inhibitors) are linked to AP. The injury begins with acinar cell hypertrophy, progress to proinflammatory cytokine induction, and culminate in pancreatic vascular injury. Exenatide has 6-fold increase risk of pancreatitis compared to other therapies. [6]

Other drugs

Clear causative association with pancreatitis also could have: L-asparaginase, corticosteroids, methyldopa, cytarabine, mercaptopurine, mesalamine, opiates, pentamidine, sitagliptin, sulfasalazine, sulindac, trimethoprim-associated sulfonamides, tetracycline. [3][7][13][14]


Substance Abuse


In 1815 was first recognised the association between heavy drinking and the development of pancreatitis. Alcohol abuse is ranked as the second most common cause of acute pancreatitis (after gallstone disease), but is well established as the single most common cause of chronic pancreatitis, with an attributable risk of 40%. [15] Several studies have postulated that the consumption of more than 80-100 g/d of alcohol for 5 years is a threshold for causing pancreatitis. [1], [16] The three major cell types in the pancreas affected by alcohol exposure include acinar cells, ductal cells and stellate cells; damage to these cells drives the acinar cell death, calcification and fibrosis of alcoholic pancreatitis. [15]

The ethanol, in chronic consumption, produces frequently AP, through different mechanisms: oversensitization of pancreatic acinar cells to cholecystokinin and premature zymogen activation, stimulation of acinar cells to overproduce enzymes that are activated prematurely because of buildup and stasis within the pancreas, formation of toxic metabolites (such as acetaldehyde and fatty acid ethyl esters (FAEEs)), increased production of reactive oxygen species or free radicals. [1], [6], [14], [15]

Activation of zymogens within the acinar cells is potentially damaging to the gland and causes autodigestion of exocrine pancreas and surrounding tissue. [2]

The non-oxidative pathway of alcohol metabolism involves the esterification of alcohol with fatty acids to form FAEEs. This reaction is catalysed by FAEE synthases. [15] These esters are lipophilic and have been shown to cause selective pancreatic acinar cell toxicity. [2] Experimental studies have demonstrated that the oxidative pathway is the predominant pathway for alcohol metabolism in the pancreas. A by-product of the oxidative pathway of alcohol metabolism is the generation of reactive oxygen species (ROS) which can cause damage to lipid membranes proteins, and cellular DNA.

Increased ROS levels associated with a concurrent depletion of anti-oxidant factors such as the ROS scavenger glutathione, leads to oxidant stress within the cell. [15]

The alcoholics have an increased tendency for protein precipitation in pancreatic juice, which is followed by stenosis, obstruction. [7], [15] The patients with alcoholic pancreatitis have raised sweat electrolyte levels, suggestive of cystic fibrosis transmembrane regulator dysfunction. The resultant increase in viscosity of pancreatic secretions could predispose to protein plug formation, and consequently, chronic changes in the pancreas. The increasing of sphincter Oddi tone (spasmogenic effect) secondary to alcohol exposure played a major role in the development of pancreatitis. [15]

Recent experimental evidence indicates that endotoxinemia (known to occur in alcoholics secondary to an alcohol-induced increase in gut mucosal permeability), may be an important co-factor in alcohol-related pancreatic injury. [15]

Alcohol per se has profound effects on pancreatic microcirculation and oxygenation. Administration of ethanol to dogs and rats reduced pancreatic blood flow and pancreatic hemoglobin saturation significantly. [16]


Tobacco exposure is an established risk factor for chronic pancreatitis and pancreatic cancer. Tobacco exposure seems to have greater detrimental effects on pancreatic function than alcohol in

some population. [17] Nicotine generates toxic metabolite cotinine (detected in pancreatic juice from smokers [18]), inhibits cholecystokinin-stimulated amylase secretion from isolated rat pancreatic acini [14], and leads to increased levels of calcium, causing cytotoxicity and eventual cell death (last effect observed in experimental animals) [8]. Also, cigarette smoke produces activation of endoplasmic reticulum stress pathways that promote acinar cell death [19], oxidative stress [1], [20], and inflammation [20].

Smoking is the major known cause of pancreatic cancer, accounting for about 25 to 30% of all cases. [8] Cigarette smoking is the only firmly established environmental risk factor for adenocarcinoma of the exocrine pancreas. [20] There are approximately 69 carcinogens among the nearly 5000 chemical constituents identified in tobacco smoke. [18] Responsible for pancreatic cancer are: nitrosamines (most common 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK)), polycyclic aromatic hydrocarbons, aromatic and heterocyclic amines (and intermediates), cadmium. [18], [20]

In mainstream smoke NNK has levels of 0.08-0.77 μg/cigarette. A smoker who smokes 20 cigarettes per day inhales approximately 9.0 μg of NNK per day. In pancreatic juice from smokers, the mean level of NNK was significantly higher than that from nonsmokers (1.37-604 ng/ml reported in a study). In rats, nitrosamines have induced acinar and ductal-cell tumors. [18] In heavy smokers, the slow acetylator N-acetyltransferase NAT2 genotype may be associated with an increased risk of pancreatic cancer. [8]

Cigarette smoke promotes cell death and features of pancreatitis in EtOH-sensitized acinar cells by suppressing the adaptive unfolded protein response signaling pathway. [19]


There are few reports of cocaine-induced pancreatitis in the literature, via vasoconstriction and thrombosis of the mesenteric vessels (thrombotic microangiopathy). [21] Cocaine inhibites cholecystokinin- and urecholine-stimulated amylase secretion, and protein synthesis also. The metabolite of cocaine and ethanol, cocaethylene exhibited a more potent inhibitory effect on amylase secretion than its parent compounds combined. [14] The pathophysiology of methamphetamines would be similar to that associated with cocaine use, by splanchnic vasoconstriction and necrotizing vasculitis. [21]



The study found increased risks for pancreatic cancer associated with increasing pesticide exposure, in particular fungicides and herbicides, but not insecticides. The workers with dichloro- diphenyl-trichloroethane exposure were about 5 times more likely to have died of pancreatic cancer. [20]

Organophosphates could affect zymogen trafficking. [3]



Manganese produces pancreatitis. [7] Pentavalent antimonials have a strong causative association with pancreatitis. [3] Cadmium in cigarette smoke is a potential pancreatic carcinogen. [20].


Scorpion venom

Scorpion toxin produces AP via altered zymogen trafficking. [3][6]


4. Conclusions

The pancreas, a retroperitoneal gland that is often quoted as an organ of mystery, may be a target for many xenobiotics which can damage both of its functions, endocrine and exocrine. Streptozocin and alloxan are the most known agents that affect endocrine function, with hyperglycemia. Are known over 120 xenobiotics (drugs, substance abuse, pesticides and other chemical agents) responsible for damage of exocrine function, via different processes. Pancreatitis is the most common clinical manifestation of pancreatic toxic aggression.


Contributo selezionato da Filodiritto tra quelli pubblicati nei Proceedings “17th Romanian National Congress oh Pharmacy – 21st Century Pharmacy – Between Intelligent Specialization and Social Responsibility - 2018”

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Contribution selected by Filodiritto among those published in the Proceedings “17th Romanian National Congress oh Pharmacy – 21st Century Pharmacy – Between Intelligent Specialization and Social Responsibility - 2018”

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