TOWARD AN ANIMAL-MODEL OF CHRONIC-PANCREATITIS - PANCREATICOBILIARY SECRETION IN HAMSTERS ON LONG-TERM TREATMENT WITH CHEMICAL INDUCERS OF CYTOCHROMES P450

There is currently no reproducible model of the painful and lithogenic disease, chronic pancreatitis. Its biphasic evolution, from acinar ce ll hyperplasia and hyperactivity toward effacement of enzyme as well a s bicarbonate secretory parenchyma, would be rationalized if it was li nked to induction of cytochrome P450 mono-oxygenases (CYP): the increa sed oxidant load from long-term CYP induction eventually erodes micron utrient antioxidant defenses to injure cells. This philosophy would al so rationalize the reported hepatobiliary aberrations associated with the human disease, including increases in free radical oxidation produ cts in bile. Accordingly, pancreatic and biliary secretions were studi ed in Syrian golden hamsters that were reared for 6 mo on low or high (16% corn oil) fat diets that were supplemented with a prototype induc er of CYP2 (200 ppm phenobarbitone) or CYP1 (100 ppm beta naphthoflavo ne) enzyme families, with or without a putative enzyme inhibitor (400 ppm cimetidine). The drugs did not alter the reduction in flowrate or bicarbonate concentration of pancreatic juice caused by the high fat d iet alone, but, in contrast, evoked pancreatic protein hypersecretion in a number of animals. beta naphthoflavone, but not phenobarbitone, a ugmented the output of biliary lipid peroxidation products irrespectiv e of dietary fat content, and cimetidine cotreatment with either induc er did the same. We conclude: (1) that drug modifiers of CYP magnify t he deleterious pancreatobiliary effects of corn oil-enriched diets and draw them closer to those found in human chronic pancreatitis; (2) th at these functional derangements are accompanied by pancreatic lipoatr ophy; and (3) that long-term CYP induction does not, of its own, cause fibrosis or the ductal abnormalities that generally accompany loss of pancreatic acinar cells in the human disease and, also in contrast, t he changes that are caused appear to be painless.