The Role Of Enzymes In Pancreatic Diseases

Chronic pancreatitis appears to be the result of exposure to xenobiotics too. Finding an increased expression of the Phase II enzyme GST-n in the islets of human patients with chronic pancreatitis compared with normal pancreas and secondary chronic pancreatitis due to duct obstruction in pancreatic cancer supported this hypothesis (see Chapter 7). 38 Lacking an animal model of chronic pancreatitis, Rutishauser et al.39 fed SGHs with a low or high fat diet that was supplemented with a prototype inducer of CYP 2 (Phenobarbitone) or CYP 1 (p-naphthoflavone) enzyme families, with or without a putative enzyme inhibitor (cimetidine). They concluded that drug modifiers of CYP magnified the deleterious effects of corn oil-enriched diets, comparable to those found in humans. Furthermore, these functional derangements were accompanied by pancreatic lipoatrophy.39 Other groups fed rats with either ethanol or 3-methylcholan-threne (MC) and investigated their influence on the activity of CYP 2E1 and CYP 1A1 in rat pancreatic microsomes. CYP 2E1 is believed to play a major role in the metabolization of ethanol, whereas CYP 1A1 is linked to the metabolism of polycyclic aromatic hydrocarbons. The results demonstrated that in pancreatic microsomes, ethanol and MC exerted striking inductive effects on CYP 2E1 and CYP 1A1 activities. These findings suggested that these enzymes play a role in the pathogenesis of pancreatitis or pancreatic cancer.40,41 Clarke et al. focused on the expression of CYP 1A-like proteins in the pancreatic islets after treatment with MC. They concluded that CYP 1A-protein was inducible in the islets and may have a role in the alteration of pancreatic p-cell responsiveness as it mediated the metabolism of arachidonic acid to metabolites with stimulating effects on insulin exocytosis.42

In rats, pancreatic carcinomas, generally of acinar appearance, could be obtained by injection of a single dose of azaserine.43,44 In this model, two distinct types of foci of abnormal acini were described — basophilic and acidophilic foci. The latter, also termed atypical acinar cell nodules (AACN) were believed to have the potential to progress to carcinoma.45,46 Daly et al. evaluated the GSTs a, and n as early immunocytochemical markers for the development of the AACN compared to haematoxylin and eosin staining (H&E). They found an overexpression of GST-^ in all foci detected with H&E. However, 64% of the foci detected with GST-^ had not been identified with H&E as AACN during a prior examination. Reevaluation of these H&E sections revealed that some of these foci showed subtle morphological changes indicative of AACNs. They concluded that immunocytochemical staining for GST-^ is a more reliable and sensitive method than H&E for detecting the early stages of azaserine-induced foci.47 An overexpression of GST-n was not found, in contrast to the reports of overexpression in pancreatic lesions induced in the hamster by nitrosamines13 and in the rat by hydroxyaminoquinoline 1-oxide.14 This might be explained by species and substrate differences.

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