Pancreatic Xanthine Research Articles

Allopurinol attenuates caerulein induced acute pancreatitis in the rat.

Oxygen derived free radicals have been implicated in the pathogenesis of acute pancreatitis in numerous animal models of the disease. The xanthine oxidase inhibitor allopurinol has been shown to attenuate pancreatic damage in canine and mouse models of acute pancreatitis presumably by preventing the generation of cytotoxic superoxide anions. We therefore examined whether allopurinol could attenuate pancreatic injury in conscious rats with caerulein induced acute pancreatitis. A continuous intravenous infusion of allopurinol (20 mg/kg/h) for six hours along with an acute pancreatitis producing dose of caerulein (10 micrograms/kg/h) reduced pancreas weights by approximately 45% and serum amylase concentrations by approximately 60% compared with rats intravenously infused with either caerulein alone or caerulein plus a lower dose (10 mg/kg/h) of allopurinol. We conclude that the generation of oxygen derived free radicals via pancreatic xanthine oxidase represents an early and perhaps pivotal mechanism in the pathogenesis of acute pancreatitis.

Xanthine oxidase activity in mouse pancreas: Effects of caerulein-induced acute pancreatitis

The development of acute pancreatitis involves a number of pathophysiological changes which result in pancreatic tissue damage. Data from several models of acute pancreatitis suggest that the in vivo conversion of the enzyme xanthine dehydrogenase to xanthine oxidase may cause tissue damage by the subsequent generation of oxygen-derived free radical products. In the present studies, acute pancreatitis was induced in mice by the administration of supramaximal secretory doses of caerulein, a cholecystokinin analogue. Pancreatic xanthine oxidase activity was observed to occur in the dehydrogenase form in both control and treated mice. Artifactual conversion to the oxidase form could be induced by exclusion of 2-mercaptoethanol and phenyl-methylsulfonyl fluoride from the buffer during tissue preparation. These data indicate that no significant conversion of xanthine dehydrogenase to oxidase is associated with this model of acute pancreatitis in mice.

Dietary and Hormonal Regulation of Pancreatic Xanthine Dehydrogenase in the Chick

Chick pancreatic xanthine dehydrogenase (PXDH) is synthesized in response to feeding. Its induction generally correlates with growth; in the absence of growth, induction is observed uniquely when pure glucose is fed. This study attempted to determine what events after feeding lead to PXDH synthesis. When chicks were fed diets providing equal numbers of calories/gram of diet and varying only in the major energy source (carbohydrate, protein, or fat), PXDH response was high in the carbohydrate-fed, low in the protein-fed, and minimal in the fat-fed chicks. A unique, transitory increase in plasma glucose occurred in the carbohydrate-fed chicks within day 2 after feeding. These unique effects of dietary glucose indicated that the induction of PXDH after feeding was linked to carbohydrate metabolism. Effects of injected insulin on PXDH were examined. Insulin doses between 0.001 and 10.0 IU induced PXDH 25-60% above the activity found in carbohydrate-fed chicks. The initiation of PXDH accumulation may be the result of a sequence of metabolic responses to dietary carbohydrate beginning with an increase in plasm glucose, which induces an insulin response.

Dietary Effects on Development of Pancreatic Xanthine Dehydrogenase in the Newly Hatched Chick

Dietary Effects on Development of Pancreatic Xanthine Dehydrogenase in the Newly Hatched Chick

Regulation of xanthine dehydrogenase levels in liver and pancreas of the chick

Xanthine dehydrogenase activity in the liver and pancreas of the chick has been shown to flactuate upon starvation and refeeding. Using combined isotope labeling an immunochemical approaches, a study has been made of the rates of synthesis and degradation of bulk soluble protein and xanthine dehydrogenase in both of these tissues. The increase in liver xanthine dehadrogenasee specific activity during starvation is due to the decrease in size of the organ with no change in the total rate of enzyme synthesis in the organ. The decrease in pancreatic xanthine dehydrogenase activity during starvation is due to a decrease in its rate of synthesis. Also, it was found that the degradation rate of bulk soluble protein in the pancreas increases during starvation. The overshoot in pancreatic xanthine dehydrogenase activity observed on refeeding appears to be due to a rapid return of xanthine dehydrogenase synthesis to normal with a slower return to normal in the rates of soluble protein degradation and synthesis.

Suppression of chick pancreatic xanthine dehydrogenase by unsaturated fatty acids

A study of pancreatic xanthine dehydrogenase levels in chicks immediately after hatching has revealed that the sharp developmental increase normally occurring can be suppressed by maintenance on whole egg ( Fisher et al., 1967; Woodward and Fisher, 1967 ). Further work has shown that ether extracts of egg yolks are equally effective in supressing this developmental increase. Of the lipid components present, four have been found to affect the accumulation of pancreatic xanthine dehydrogenase: linolenic, linoleic, and oleic acids suppress and stearic acid enhances. It seems reasonable to believe that the suppressing activity of ether extracts of eggs is due to the presence of unsaturated fatty acids. The administration of specific fatty acids leads to increased concentrations of these materials in the lipids of the pancreas.

Control of pancreatic xanthine dehydrogenase synthesis in the chick

1. 1. Previously it has been shown that the level of xanthine dehydrogenase activity in the pancreas of the thick is under control of some agent(s) in the diet. When food is withheld activity falls with a half-life of 30 h and rises sharply upon re-feeding. Specific and total activities rise to almost double the steady-state level after re-feeding and then slowly return to the level of continuously fed controls. 2. 2. Pancreas slices incubated in a tissue culture medium incorporate labeled amino acids into xanthine dehydrogenase and the rate of incorporation depends upon the dietary history of the animals used. The rate of incorporation into total protein is essentially independent of this dietary history.

Control of xanthine dehydrogenase in the chick pancreas

Fisher et al. (1967) have shown that pancreatic xanthine dehydrogenase in newly hatched chicks is induced by feeding whereas this enzyme in the liver, kidney, and duodenum is unaffected by the ingestion of food. This induction is due to some substance(s) in the feed and not to the nutritional balance of the diet. An extensive examination of the pancreatic system has shown that there is a 3000-fold increase in total activity between day 19 (2 days before hatching) and day 15 after hatching with chicks fed a normal diet. Unfed chicks exhibit an activity of 0.4% of maximum value and egg-fed chicks a level of 6.3%. Between the second and third weeks after hatching, specific activity in the pancreas decreases to about one-half the maximum level. When these older chicks are fasted or fed egg, activity falls and refeeding the normal diet causes a sharp increase in activity to a level double that of continuously fed chicks. These results indicate that some change occurs in pancreatic tissue slightly before hatching which allows enzyme production, and after this time activity is controlled by a dietary inducer and a “repressing effect” formed in response to the inducer.

Developmental changes and control of xanthine dehydrogenases in developing chicks

Developmental changes in xanthine dehydrogenase activity of liver, kidney, pancreas, and duodenum have been described. Activity is high in the kidney before hatching, but nevertheless there is a significant increase at hatching. Activities in the liver and duodenum increase sharply at hatching and activity in the pancreas increases subsequent to hatching. Injection of pituitary extracts into developing eggs on days 16, 17, and 18 results in a precocious increase in liver xanthine dehydrogenase activity observed on day 19. The agent responsible has not yet been identified. The increase in pancreatic xanthine dehydrogenase is dependent upon feeding after hatching whereas activity in other tissues studied is not. Apparently the act of feeding itself or some component in the diet induces this response. These studies indicate that at least three different control mechanisms for xanthine dehydrogenase are present in chicks.