Toxicology of the Exocrine Pancreas

Abstract

The exocrine pancreas is not a common target organ for toxic drugs and chemicals. It is however the fifth most common human cancer in the western world, and acute and chronic pancreatitis, through various identifiable and unidentified causes, is a common disease in both the developed and developing countries of the world. Both inflammatory disease and cancer of the pancreas is correlated to lifestyle with poor diet and habits, such as moderate to high alcohol intake and smoking, having positive correlations to developing the disease. The chapter describes the functional anatomy of the organ together with its biochemistry that determines toxicity, in particular the role of oxidant damage in the development of cell and tissue damage is thought to be important. The consequences of toxic damage to the acinar cells are severe and primarily result from the auto‐activation and hence autodigestion of the tissue by the digestive enzymes normally contained within the exocrine cells, a cascade of apoptosis/necrosis and fibrosis with the ultimate collapse of the organ, subsequent shock, multi‐organ collapse and death. The organ has complex molecular mechanisms to prevent premature activation of the digestive enzymes and also has defence mechanisms present to neutralise any premature enzyme activation but these can be rendered ineffectual by factors such as alcohol abuse and a poor diet. Chemical exposure, through both occupational and consumer product usage, has been associated with the development of both pancreatic neoplastic and non‐neoplastic disease but the relationship between exposure and disease has never developed further than a simple association and it is likely that the development of pancreatic disease is a multi‐faceted combination of inter‐related events, none of which in isolation can induce disease. The pancreas has its own array of phase 1 and 2 metabolic enzyme systems and the role of pancreatic drug and chemical activation and detoxification in inducing toxicity is discussed together with the possible secondary effects of hepatic drug/chemical activation and detoxification. Finally the role of animal models of pancreatic disease is discussed in terms of their contribution to understanding the aetiology of the human conditions and the possible use of therapeutic intervention in treating the disease.

A Review of Animal Models of Nonneoplastic Pancreatic Diseases

“…Since this time, a number of animal models have been developed, which show varying degrees of faithfulness to the developing lesions in man and which have been used to address the possibility of therapeutic intervention to modify the course of the disease (Büchler et al 1992; Al-Mufti and Williamson 1999; Lerch and Adler 1994). The ability to investigate the development of the disease, following a known insult, has significantly contributed to our understanding of the underlying pathogenesis of the human disease and have guided some of the available therapies in use today (Foster 2009). The animal models that are readily available tend to be in rodents, although useful models have been developed in the dog, the possum, and the cat (Lerch et al 1992; Su, Cuthbertson, and Christophi 2006; Wedgwood, Farmer, and Reber 1986).…”

Micronutrient ('Antioxidant') Therapy for Chronic Pancreatitis: Basis and Clinical Experience

“…Analysis of secretin-stimulated duodenal aspirates identified Increased lipid peroxidation, albeit less than in chronic pancreatitis (68). Dietary inventories showed that datapoints lay on or close to the aforementioned discrimination line based on selenium intake versus theophylline clearance (54). Oxidative stress is recognized in the pathogenesis of recurrent pancreatitis due to deficiency of lipoprotein lipase (69).…”