Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxygen-derived free radicals play an important role in the pathogenesis of experimental acute pancreatitis in the isolated perfused canine pancreas. We have previously found that pretreatment with allopurinol inhibits xanthine oxidase--apparently the primary source of free radical generation in this model--and prevents the initial development of pancreatitis. In these experiments, we evaluated whether allopurinol administered after the onset of pancreatitis would arrest the progression of the disease process. Edema formation, weight gain, and the release of amylase activity into the perfusate in the ex vivo perfused canine pancreas model were monitored during a 4-hour perfusion period. There were six experimental groups: Group I (control) received no treatment, group II (allopurinol alone) received only allopurinol (100 mg) at the start of perfusion, and groups III through VI were each given an infusion of 0.3 ml of oleic acid (FFA) over a 1-hour period to initiate acute pancreatitis. Group III (FFA alone) received no other treatment. In group IV (pretreatment with allopurinol), group V (concurrent treatment with allopurinol), and group VI (posttreatment with allopurinol), allopurinol (100 mg) was administered 1 hour before, concurrent with, or at the end of the FFA infusion, respectively. Pretreatment with allopurinol prevented edema formation, markedly attenuated weight gain, and the release of amylase caused by the FFA infusion. Administration of allopurinol concurrent with the FFA infusion provided only partial protection, whereas posttreatment with allopurinol failed to arrest the progression of the injury process. Therefore, the use of allopurinol to inhibit oxygen-derived free radical production from xanthine oxidase prevented the development of acute pancreatitis in this model; however, treatment with allopurinol after initiation of the disease process failed to arrest the progression of acute pancreatitis.
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PMID:Temporal efficacy of allopurinol during the induction of pancreatitis in the ex vivo perfused canine pancreas. 382 61

The luteolytic mechanism was investigated in rat corpora lutea (CL). This study focused on the changes that occur in the plasma membrane. Previous experiments with rat luteal cells indicated that in vitro generation of superoxide radicals by xanthine oxidase disrupted LH-stimulated cAMP production and progesterone secretion similar to the effect of prostaglandin F2 alpha, the luteolytic hormone. In the present study, we observed that xanthine oxidase treatment of plasma membrane samples from CL caused a large decrease in fluidity, which also occurs during prostaglandin F2 alpha-induced luteolysis. This fluidity change was blocked by catalase, bromophenacyl bromide, an inhibitor of phospholipase-A activity, indomethacin, and free radical scavengers, and it was reversed by removal of FFA from the membrane. In addition, xanthine oxidase treatment caused phospholipid breakdown, formation of neutral lipids, a burst of inorganic peroxides, and a sustained rise in the level of lipid peroxides. These results indicate that free radical generation causes several changes that disrupt the plasma membrane of CL cells, and they raise the possibility that phospholipid breakdown could be involved in the mechanism that inhibits LH stimulation of steroidogenesis during luteolysis.
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PMID:Plasma membrane changes in the rat corpus luteum induced by oxygen radical generation. 834 94

Four models of acute pancreatitis have been previously developed that use the ex vivo perfused isolated canine pancreas preparation. The four models include the intraarterial infusion of oleic acid (FFA) that mimics hyperlipemic pancreatitis, partial obstruction of the pancreatic duct with secretin stimulation (POSS) that mimics gallstone pancreatitis, a 2-hour period of ischemia before perfusion (ISCH 2) that mimics shock pancreatitis, and the infusion of cerulein at supramaximal stimulatory doses (CER), which lacks an obvious clinical counterpart. In the FFA, POSS, and ISCH 2 pancreatitis, but not in the CER pancreatitis, toxic oxygen metabolites, generated by the enzyme xanthine oxidase (XO), have been shown to be important mediators in the early pathogenesis. Ordinarily XO primarily occurs as xanthine dehydrogenase (XD) but can be converted to XO, which is the form that generates toxic oxygen metabolites. This conversion of XD to XO may take place either reversibly by way of sulfhydryl group oxidation or irreversibly by means of proteolytic cleavage of XD. This study was undertaken to investigate the mechanism of conversion of XD to XO in the FFA-, POSS-, and ISCH 2-induced pancreatitis models. CER pancreatitis was studied for comparison. After 4 hours of perfusion, pancreatitis was manifest by edema, weight gain, and hyperamylasemia in all four models. Dithiothreitol, a sulfhydryl group protector, ameliorated the weight gain in the FFA (40 +/- 14 gm to 18 +/- 13 gm; p < 0.05), POSS (28 +/- 10 gm to 9 +/- 3 gm; p < 0.05), and ISCH 2 pancreatitis (30 +/- 13 gm to 15 +/- 3 gm; p < 0.05), and ameliorated the hyperamylasemia in the POSS pancreatitis (12,062 +/- 4304 units/dl to 5877 +/- 2659 units/dl; p < 0.05). The CER pancreatitis was not ameliorated with dithiothreitol. A serine protease inhibitor of low molecular weight, phenylmethylsulfonyl fluoride, ameliorated only the CER pancreatitis (weight gain from 28 +/- 10 gm to 17 +/- 10 gm, p < 0.05; amylase activity from 38,116 +/- 6491 units/dl to 23,372 +/- 11,654 units/dl, p < 0.05), and not the FFA, POSS, or ISCH 2 pancreatitis. We conclude that in the three models of pancreatitis (FFA, POSS, and ISCH 2) that are mediated by toxic oxygen metabolites, XD is converted to XO reversibly by way of sulfhydryl group oxidation rather than irreversibly by way of proteolysis. In the CER pancreatitis, where XO does not play a role in the pathogenesis, proteolytic enzymes may be important mediators in the injury.
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PMID:The mechanism of conversion of xanthine dehydrogenase to xanthine oxidase in acute pancreatitis in the canine isolated pancreas preparation. 841 95