Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.4 (trypsin)
42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was undertaken in order to improve photoaffinity labelling efficiency of pancreatic cholecystokinin receptor by the cleavable probe 125I-ASD-(Thr28,Ahx31)-CCK-25-33 and to further characterize the denaturated receptor and its agonist binding domain. Membrane bound pancreatic cholecystokinin receptor was specifically labelled by 125I-ASD-(Thr28,Ahx31)-CCK-25-33 as a component of Mr approximately 85,000-100,000. The efficiency of the photolabelling was 3-4%. Performing photolysis on [125I-ASD-(Thr28,Ahx31)-CCK-25-33-receptor] complexes solubilized by CHAPS did not affect specificity of the labelling reaction but enhanced its efficiency so that up to 10% of the receptor site population could be cross-linked. Several lectins were tested for their ability to recognize and purify the cholecystokinin receptor denaturated by Nonidet P-40. Wheat germ agglutinin provided the best recovery and purification rate. The receptor was fully adsorbed on immobilized wheat germ agglutinin, while only a fraction was retained on ricin II (28%) and Ulex europaeus (58%), thus suggesting that the receptor is heterogeneously glycosylated. Finally, major labelled receptor fragments were generated by enzymatic digestion. There were: endoproteinase Glu-C----Mr approximately 34,000; endoproteinase Glu-C/trypsin----Mr approximately 12,000; chymotrypsin/endoproteinase Glu-C----Mr approximately 16,000 and 12,000. The fragment of Mr approximately 34,000 was deglycosylated to a component of Mr approximately 22,000 whereas the other fragments were insensitive to deglycosylation Such results strongly suggest that cholecystokinin binding occurs in a non-glycosylated domain of the cholecystokinin receptor protein.
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PMID:Biochemical characterization of a subtype pancreatic cholecystokinin receptor and of its agonist binding domain. 158 23

We conducted a 14 day experiment in which we administered camostate (a trypsin inhibitor) and cholecystokinin alone or in combination with lorglumide, a cholecystokinin receptor antagonist, to both rats and hamsters. Plasma cholecystokinin levels were 21.7 +/- 3.2 pM and 19.6 +/- 2.5 pM with camostate, 16.3 +/- 2.4 pM and 14.8 +/- 2.2 pM with exogenous cholecystokinin, and 3.7 +/- 0.4 pM and 4.2 +/- 1.0 pM in control experiments in rats and hamsters, respectively. Both cholecystokinin and camostate were found to promote pancreatic growth in rats (18 +/- 4 and 111 +/- 7%, respectively) and hamsters (76 +/- 18 and 61 +/- 12%, respectively). Although lorglumide caused a decrease of this effect of camostate in both rats (78 +/- 5%) and hamsters (25 +/- 10%), it only became significant in rats. We therefore conclude that there are important interspecies differences in the role cholecystokinin plays in mediating the trophic effects of trypsin inhibitors on the pancreas.
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PMID:Comparison of the effect of lorglumide on pancreatic growth stimulated by camostate in rat and hamster. 230 71

The present study evaluates the effect of atropine and of the cholecystokinin receptor antagonist loxiglumide on feedback regulation of basal pancreatic secretion in 6 healthy volunteers. The intraduodenal instillation of the protease inhibitor camostate reduced enzymatic activities of trypsin and chymotrypsin by 80%. This was accompanied by a strong increase in amylase and lipase output. The intravenous infusion of atropine (5 micrograms/kg.h) completely abolished the stimulatory effect of camostate on enzyme output. The infusion of loxiglumide (10 mg/kg.h) caused no changes in camostate-induced stimulation of enzyme output. Plasma levels of cholecystokinin were not altered after intraduodenal instillation of camostate whether atropine, loxiglumide, or saline were infused. We suggest that the protease inhibitor camostate, by inhibition of the enzymatic activity of trypsin and chymotrypsin, interferes with feedback regulation of basal pancreatic secretion in humans, and this mechanism is predominantly mediated by the cholinergic system.
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PMID:Differential effects of atropine and a cholecystokinin receptor antagonist on pancreatic secretion. 264 76

Feeding of raw soya flour or other trypsin inhibitors such as camostate is a well-established method for promoting growth of (pre)neoplastic foci induced in the exocrine pancreas of rats by azaserine. The effect of trypsin inhibitors is thought to be mediated through an increased release of cholecystokinin. Using the specific cholecystokinin receptor antagonist lorglumide (CR-1409), we performed a 16-wk study to investigate the potential of this drug in inhibiting growth of putative preneoplastic foci and to determine whether and to what extent cholecystokinin is responsible for the effect of trypsin inhibitors on pancreatic growth. After initiation with 30 mg/kg of azaserine at 19 days of age, six groups of 15 rats each received one of the following treatments: camostate, cholecystokinin-8, or gelatin control, either or not in combination with CR-1409, once daily, 3 days wk for 16 wk. Plasma cholecystokinin levels, measured 30 min after the stimulus, were similar after camostate and cholecystokinin octapeptide administration. After 16 wk the pancreata were removed, weighted, and quantitatively analyzed for the number and size of putative preneoplastic foci by light microscopy. Both camostate and cholecystokinin octapeptide stimulated pancreatic growth and development of acidophilic putative preneoplastic foci, whereas growth of basophilic putative preneoplastic foci was inhibited by camostate but stimulated by cholecystokinin. CR-1409 almost completely abolished the effect of cholecystokinin and was found to cause a significant decrease in the effects of camostate. It is concluded that (a) cholecystokinin plays a significant role in camostate-stimulated growth of acidophilic putative preneoplastic foci in rat pancreas and (b) CR-1409 inhibits growth of putative preneoplastic foci induced in rat pancreas by azaserine and hence may be of potential value for the treatment of pancreatic cancer in humans.
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PMID:Modulation by CR-1409 (lorglumide), a cholecystokinin receptor antagonist, of trypsin inhibitor-enhanced growth of azaserine-induced putative preneoplastic lesions in rat pancreas. 270 31

Chronic feeding of rats with camostate results in pancreatic hypertrophy or hyperplasia, or both. Previous studies suggest that this effect of camostate occurs via an increase in endogenous cholecystokinin due to an enteral feedback mechanism involving the inhibition of trypsin in the duodenum. Studies employing proglumide, a weak and relatively nonspecific cholecystokinin antagonist, have failed to fully abolish camostate-induced pancreas growth. We examined the effects of L-364,718, a new and highly potent cholecystokinin receptor antagonist, on camostate-induced pancreas growth in rats. The pancreas weights and the concentrations of ribonucleic acid, protein, and chymotrypsinogen in the pancreas of rats treated with camostate alone were significantly elevated over those of controls. These effects of camostate were completely abolished in rats treated with camostate + L-364,718. The pancreas weights and the concentrations of deoxyribonucleic acid and ribonucleic acid in the pancreas of rats treated with L-364,718 alone were significantly lower than values in control rats. These data indicate that camostate-induced pancreas growth in rats appears to be dependent on the actions of endogenous cholecystokinin and that cholecystokinin may play a role in the maintenance of pancreatic growth in normal rats.
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PMID:Effects of L-364,718, a new cholecystokinin receptor antagonist, on camostate-induced growth of the rat pancreas. 333 82

Venom from Gila monster (family Helodermatidae) contains a pancreatic secretagogue. In dispersed acini from guinea pig pancreas, the venom increased enzyme secretion to the same extent as did vasoactive intestinal peptide, secretin, or PHI. The abilities of vasoactive intestinal peptide and Gila monster venom to stimulate enzyme secretion were not altered by boiling but were abolished by incubation with trypsin or chymotrypsin. Like vasoactive intestinal peptide, secretin, and PHI, the venom caused a 50- to 60-fold increase in cellular cAMP and inhibited binding of 125I-vasoactive intestinal peptide to its membrane receptors on pancreatic acini. The action of venom on enzyme secretion was inhibited by [Gln9]secretin-(5-27), a vasoactive intestinal peptide receptor antagonist, but was not altered by atropine, a cholinergic receptor antagonist, or by dibutyryl cGMP, a cholecystokinin receptor antagonist. Gila monster venom contained no immunoreactive vasoactive intestinal peptide by radioimmunoassay. These results indicate that venom from Gila monster contains a peptide that can stimulate pancreatic enzyme secretion by interacting with vasoactive intestinal peptide receptors on pancreatic acinar cells and thereby activating adenylate cyclase and increasing cellular cAMP.
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PMID:Actions of Gila monster venom on dispersed acini from guinea pig pancreas. 617 52

The new CCK-B/gastrin receptor antagonist PD 136450 is of potential value in treating neurologic and psychiatric disorders. We investigated possible side effects on the rat pancreas using acute and chronic administration schedules. In chronic experiments, four groups of rats were given either PD 136450, the proton pump inhibitor BY 308 (in order to induce hypergastrinemia), a combination of both, or control solutions over 14 d. Pancreatic growth, DNA, and protein content were significantly increased in rats given PD 136450 irrespective of circulating gastrin levels. Furthermore, an anticoordinate shift in pancreatic enzyme content in favor of trypsin and chymotrypsin at the expense of amylase and lipase was observed. Plasma CCK levels remained unchanged in this group making a role of circulating hormone unlikely. In order to investigate a possible direct agonist effect of the CCK-B/gastrin receptor antagonist, we studied amylase release from isolated rat pancreatic acini in response to PD 136450 and sulfated CCK8 alone and in combination with the specific CCK-A receptor antagonist MK 329. Increasing concentrations of PD 136450 caused a monophasic dose-response curve in contrast to the well-known biphasic amylase release in response to CCK8. Addition of increasing doses of PD 136450 to a concentration of CCK causing maximal stimulation of amylase release (0.1 nM) further enhanced amylase release from pancreatic acini. The specific CCK-A receptor antagonist MK 329 dose-dependently inhibited CCK8- and PD 136450-induced amylase release. In conclusion, the new CCK-B/gastrin receptor antagonist PD 136450 exhibited profound agonist actions on the rat pancreas mediated via CCK-A receptors.
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PMID:A new CCK-B/gastrin receptor antagonist acts as an agonist on the rat pancreas. 752 49

Effects of long-term administration of the cholecystokinin receptor antagonist loxiglumide on exocrine pancreas were studied in adult rats. Plasma concentrations of loxiglumide at 8 h after a single subcutaneous injection of 50 mg/kg body weight of loxiglumide were 3.2 +/- 0.8 microgram/ml, which were comparable to those at 12 h after oral administration of the same dose (3.7 +/- 0.9 microgram/ml). Eight hours' prior subcutaneous injection of loxiglumide (50 mg/kg body weight) significantly suppressed pancreatic exocrine secretion stimulated by an intravenous bolus injection of 50 ng/kg body weight caerulein compared with the control rats. Based on these results, in the first experiment, loxiglumide at a dose of 50 mg/kg body weight was given subcutaneously three times a day (low dose) for 6 days to adult rats fed a standard laboratory diet. Low dose of loxiglumide significantly decreased pancreatic wet weight (-14%) and pancreatic contents of protein (-26%), trypsin (-38%), and lipase (-68%), while having no significant effect on pancreatic contents of DNA and amylase. In the second experiment, three times higher dose of loxiglumide (150 mg/kg body weight) was given by an orogastric tube twice daily for 6 days. High dose of loxiglumide significantly decreased pancreatic weight (-11%) and contents of protein (-20%) and DNA (-22%), whereas it significantly increased amylase (+92%) and trypsin content (+20%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of cholecystokinin receptor antagonist loxiglumide on rat exocrine pancreas. 793 91

Several peroxisome proliferators have been shown to produce pancreatic acinar cell hyperplasia/adenocarcinomas in 2-year bioassays with rats: ammonium perfluorooctanoate (C8), clofibrate, methylclofenapate, HCFC-123, and Wyeth-14,643 (WY). We have used in vitro (C8, WY) and in vivo (WY) approaches to examine several possible mechanisms of pancreatic tumorigenesis by peroxisome proliferating compounds. These mechanisms include cholecystokinin receptor agonism (CCK(A)), trypsin inhibition, alterations in gut fat content, cholestasis, and altered bile flow/composition. All of these mechanisms enhance pancreatic growth either by binding to the CCK(A) receptor or by increasing plasma CCK levels. In vitro experiments using a receptor competition binding assay demonstrated that WY and C8 do not bind directly to the CCK(A) receptor. In a continuous spectrophotometric assay, WY and C8 also failed to inhibit trypsin, a common mechanism for increasing plasma CCK levels. These in vitro results suggested that WY was not acting via the two most common mechanisms for modulation of pancreas growth. Two types of in vivo experiments were conducted. The subchronic study (2-month duration) was designed primarily to detect early changes in pancreatic growth such as those mediated by compounds that inhibit trypsin or act as CCK(A) receptor agonists. The chronic study (6 months) was designed primarily to evaluate whether the pancreatic lesions were secondary to hepatic changes such as cholestasis and/or altered bile flow/composition. In the in vivo experiments, male Crl:CDBR rats were fed diets containing 0 or 100 ppm WY. In the subchronic study WY-treated rats had a twofold increase in mean relative liver weights, an eightfold increase in hepatic peroxisomal proliferation, and a fourfold increase in hepatocyte cell proliferation after 1 week which remained elevated throughout the 2 months of treatment. In contrast, no pancreatic weight effects, increases in plasma CCK, or acinar cell proliferation was seen through 2 months in the WY group when compared to the control group. Fecal fat concentrations were also measured at 2 months and demonstrated no difference between control and WY-treated animals. The absence of any early pancreas changes in the subchronic study is consistent with the in vitro data which demonstrated that WY is not a CCK(A) agonist or a trypsin inhibitor. The chronic study demonstrated increases in pancreatic weights at 3 months (6% above control) and 6 months (17% above control), as well as increased CCK plasma levels in the WY-treated group. Liver effects in the chronic study paralleled those of the subchronic time points. Clinical pathology endpoints including increased serum concentrations of bile acids, alkaline phosphatase, and bilirubin were indicative of cholestasis in the chronic WY-treated group. The cholestasis may be responsible for the downward trend in total bile acid output, both of which may contribute to the modest increases in plasma CCK levels. These results indicate that chronic exposure to WY causes liver alterations such as cholestasis, which may increase plasma concentrations of CCK. Hence, WY may induce pancreatic acinar cell adenomas/adenocarcinomas via a mild but sustained increase in CCK levels secondary to hepatic cholestasis.
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PMID:Mechanisms for the pancreatic oncogenic effects of the peroxisome proliferator Wyeth-14,643. 926 17

The effects of a new benzodiazepine-derivative, cholecystokinin receptor antagonist, TS-941, on experimental acute pancreatitis were studied in rats. Hemorrhagic pancreatitis was induced by an infusion of a mixture of trypsin and taurocholate into the pancreatic duct. Edematous pancreatitis was induced by intraperitoneal injection of 40 microg/kg body weight of cerulein at 0 and 1 h after the start of the experiment. TS-941 (3 mg/kg) was injected subcutaneously immediately and 3 h after the induction of pancreatitis. In trypsin-taurocholate-induced pancreatitis, TS-941, with or without the synthetic trypsin inhibitor ONO-3403, had no beneficial effects on the survival rate, pancreatic wet weight, and serum pancreatic enzymes. In cerulein-induced pancreatitis, the treatment with TS-941 significantly reduced the increases of pancreatic wet weight and serum amylase and lipase. Plasma trypsinogen activation peptide (TAP) significantly rose 1 h after the first injection of cerulein. TS-941 inhibited the liberation of TAP in cerulein-induced pancreatitis. These results show that TS-941 is effective for prevention of cerulein-induced edematous pancreatitis. ONO-3403 has beneficial effects on trypsin-taurocholate-induced hemorrhagic pancreatitis, but the combination of TS-941 and ONO-3403 has no additive effect.
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PMID:Effects of a new cholecystokinin antagonist, TS-941, on experimental acute pancreatitis in rats. 978 44


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