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PubMed1988

Degradation of human epidermal keratin by fish pepsin.

Stomach extract of Atlantic herring Clupea harengus, Atlantic salmon Salmo salar, cod Gadus morhua, redfish Sebastes marinus, and plaice Pleuronectes platessa, degraded human epidermal keratin effectively in vitro. The keratin-degrading activity of all extracts showed a pH optimum around 3.3-3.4, and sheets of plantar callus were degraded with about the same efficacy as keratin. Pepstatin sensitivity, heat lability, and the acidic pH optimum demonstrated that the keratin-degrading activity was pepsin. The keratin-degrading activity of cod stomach extract had a temperature optimum of around 42 degrees C at optimal pH, and showed a similar pH dependency with collagen as with keratin as substrate. The keratin-degrading activity of pepsin I and pepsin II purified from cod showed a pH optimum of 3.7 and 3.1, respectively, similar to that obtained with hemoglobin as substrate. Pig pepsin showed a pH optimum of about 2 with keratin, hemoglobin, and collagen as substrates. The present investigation demonstrates that fish pepsin is effective in degrading human epidermal keratin in vitro, and in a contemporary study the same was shown with fish trypsin. This may suggest a possible mechanism for the development of irritative hand eczema caused by exposure to fish and acidified fish material.

Animals↗

PubMed1988

Effect of high dose omeprazole on gastric pepsin secretion and serum pepsinogen levels in man.

To investigate the effect of omeprazole on serum and urinary pepsinogens and on gastric pepsin, 8 healthy male volunteers were studied before and after 9 days of treatment with omeprazole 60 mg/day p.o. Fasting serum samples and 24 h urine specimens were obtained, and gastric contents were aspirated at 15-min intervals, 4 prior to and 6 during pentagastrin 1.5 micrograms.kg-1.h-1 i.v. during intra-gastric perfusion with NaCl 0.9% and phenol red 3 mg.ml-1 as an inert recovery marker. Basal and pentagastrin-stimulated volume and acid secretion were significantly decreased. The basal and pentagastrin stimulated pepsin output remained unchanged but pepsin concentration in gastric secretion was increased. Administration of omeprazole resulted in a significant increase in the serum PGA and PGC levels. The 24-h urinary excretion of PGA increased, but that of PGC remained unchanged, and so did the renal clearances of creatinine and pepsinogen A. The renal clearance of pepsinogen C decreased. It was concluded that omeprazole did not affect gastric pepsin output, but, due to the decreased volume output, the concentration of pepsin in the gastric secretion was increased. Omeprazole increased the serum levels of pepsinogen A and C because more pepsinogen was released into the systemic circulation. This might be due to greater back-diffusion of pepsinogen from the gastric mucosa into the systemic circulation as a result of the higher pepsinogen concentration in gastric secretion.

Administration, Oral↗

PubMed1986

Effect of single and repeated doses of oral omeprazole on gastric acid and pepsin secretion and fasting serum gastrin and serum pepsinogen I levels.

The effect of omeprazole on gastric acid and pepsin secretion and fasting serum gastrin and serum pepsinogen I levels was studied in 12 healthy volunteers. Omeprazole, 40 mg enteric-coated granules, or placebo was given once daily for nine days in a double-blind crossover study design. Twenty-four hours after a single dose of omeprazole, mean basal and mean pentagastrin-stimulated acid output decreased significantly. This effect was more pronounced after nine days of treatment. Basal pepsin output was significantly reduced only in those subjects with basal anacidity during omeprazole treatment. Stimulated pepsin output was slightly reduced after a single dose but unaltered after nine days of omeprazole. Fasting serum gastrin and serum pepsinogen I levels increased significantly during omeprazole treatment. It is concluded that omeprazole is a potent and selective inhibitor of gastric acid secretion, probably without a direct effect on pepsin secretion. However, in cases of basal anacidity during omeprazole administration, basal pepsin secretion is reduced. During omeprazole treatment, fasting serum levels of gastrin and pepsinogen I rise.

Administration, Oral↗

PubMed1988

Importance of pepsin and stomach distension in morphological alterations of stress-induced gastric lesions in pylorus-ligated rats.

Pylorus ligation changed the morphology and location of gastric lesions induced by water-immersion stress (WI stress) in rats; linear lesions in the corpus mucosa disappeared, and punctate lesions appeared in both the corpus and antrum, in association with the loss of H+ and the gain of Na+ in the gastric contents. Oral administration of antipeptic drugs such as amylopectin sulfate and sulfated glyptide or porcine pepsin significantly prevented or aggravated the lesions, respectively, although another type of elongated lesion appeared in response to high doses of antipeptic drugs. These antipeptic drugs or exogenous pepsin significantly reduced or increased pepsin activity, respectively, without effect on the acid output. Similar punctate lesions were produced in the atropinized rats (10 mg/kg) by instillation of acid solution (100 mM HCl plus 54 mM NaCl) with pepsin into the pylorus-ligated stomach and subjecting to WI stress. On the other hand, when the gastric contents were drained through a fistula to prevent accumulation of gastric juice in the pylorus-ligated stomach, WI stress again induced linear lesions only in the corpus mucosa. Acid hypersecretion in these rats induced by intravenous infusion of histamine, tetragastrin, or carbachol significantly aggravated the severity of lesions but did not change their morphology. These results suggest that pepsin in the presence of acid is prerequisite for development of gastric lesions in pylorus-ligated rats induced by WI stress. The morphological alterations may be accounted for by the distensions of the stomach due to accumulation of gastric juice in the lumen caused by pylorus ligation, but not due to acid hypersecretion.

Animals↗

PubMed1985

Comparison of the effects of structurally different H2-antagonists on acid and pepsin activity stimulated by dimaprit in conscious cats.

In the present study the effects of three structurally different H2-receptor antagonists (cimetidine, ranitidine and oxmetidine) have been investigated on gastric acid and pepsin secretion of eight cats provided with cannulated gastric fistulas. The maximum pepsin output obtained from a set of complete dose-response curves of dimaprit was not statistically different from basal values. In the presence of the H2-antagonists, while the gastric acid secretion induced by dimaprit was competitively antagonized, the pepsin secretion was differently affected. The data obtained on pepsin activity with cimetidine and ranitidine were quite similar to the control values. By contrast, oxmetidine induced a significant increase. The results suggest a very weak involvement of the H2-receptors in pepsin activity and that oxmetidine performance could not be attributable to an H2-receptor block.

Animals↗

PubMed1979

Inhibition of pepsin secretion by metiamide and atropine in the conscious rat.

The inhibition of pepsin secretion by metiamide and atropine has been studied in the gastric fistula rat and the Heidenhain pouch rat. A comparison of the effectiveness of metiamide and atropine in inhibiting pepsin secretion was made by using doses of the antagonists which produced a similar level of inhibition of acid secretion. In the gastric fistula rat both atropine and metiamide inhibited the basal pepsin output, but atropine was more effective than metiamide in this respect. In the Heidenhain pouch rat a large dose of metiamide which inhibited bethanechol-stimulated acid secretion had no significant effect on the corresponding output of pepsin. In this preparation atropine inhibited both acid and pepsin secretion. Possible reasons for the differences in the two preparations are discussed.

Animals↗

PubMed1981

Effect of topical application of amino acids on gastric pepsin secretion in the rat. Part II: effect of pH changes and glycine in separate perfusion preparation.

Gastric acid and pepsin were measured in antrum and fundus separately by perfusing each region of the stomach in anaesthetized rats. Perfusion of the antral region with alkaline and acid solutions did not affect gastric acid and pepsin secretions in the fundic gland region. Gastric secretions in the antrum and acid secretions in the fundus remained unchanged when each region of the stomach was instillated with glycine. Pepsin stimulation was observed in the fundic region only when perfused with glycine. We confirmed our previous observation that topical amino acid in the oxyntic gland stimulated pepsin secretion directly. The pepsin stimulatory effect of amino acid was found to be independent of antral regulation.

Administration, Topical↗

PubMed1983

Limited proteolysis as a tool to study the kinetics of protein folding: conformational rearrangements in acid-dissociated lactic dehydrogenase as determined by pepsin digestion.

Noncovalent aggregation as a side reaction competing with the reconstitution of oligomeric enzymes is enhanced by slow conformational changes within the partially unfolded subunits. This has been shown for lactic dehydrogenase from pig muscle after acid dissociation [G. Zettlmeissl, R. Rudolph, and R. Jaenicke (1981) Eur. J. Biochem. 121, 169-175]. The present experiments confirm previous spectroscopic evidence (from circular dichroism) applying pepsin digestion and subsequent analysis of the fragments on sodium dodecyl sulfate-polyacrylamide gradient gels. The susceptibility of certain fragmentation sites toward pepsin digestion changes with increasing incubation at acid pH, in accordance with a slow M1 leads to M2 transition of the acid-dissociated monomers. Constant pulses of pepsin at varying times after transferring native enzyme to pH 2.3 yield distinct changes in the fragmentation pattern consisting of undigested monomers (Mr = 35,000) plus 12 fragments ranging from 31,000 to 5000. Short digestion of the M2 species at low concentrations of pepsin preferentially yields 25,000 and 10,500 fragments (molar ratio pepsin:lactic dehydrogenase = 1:24). The time-dependent decrease of monomers upon incubation in 0.1 M sodium phosphate, pH 2.3, at 20 degrees C strictly parallels the formation of the two fragments. The quantitative kinetic analysis of the changes in peptide pattern yields a first-order rate constant k1 = 8 +/- 2 X 10-4 s-1. The observed increase in proteolytic susceptibility is in the time range of the above mentioned decrease in the far-ultraviolet circular dichroism, and the parallel decrease in the yield of reactivation. The results suggest that during the M1 leads to M2 transition at acid pH a specific interdomain cleavage site is becoming exposed. As taken from the molecular weight of the two main fragments the trp 225-lys 226 peptide bond is the most probable candidate for this cleavage site.

Animals↗

PubMed1978

Properties of the activation by pepsin of inactive renin in human amniotic fluid.

1. The renin present in human amniotic fluid was found to have an apparent Mr of 58 000 by gel filtration and is thus bigger than renin in untreated kidney extracts and plasma (Mr approximately 40 000). 2. Treatment with pepsin (40 microgram/ml pH 4.8, 2 h, 22 degrees C) caused a 6-fold increase in activity of this renin species, although Mr was not very different (57 000). 3. Unlike renal renin, renin in human amniotic fluid was not a glycoprotein and behaved similarly on concanavalin A-Sepharose before and after activation by pepsin. 4. Ion-exchange chromatography demonstrated a small change in the ionization properties of human amniotic fluid renin after activation by pepsin. 5. Pepsin-mediated activation resulted in a five-fold increase in V, but only a small decrease in the Km of renin to 39% of normal, so that the increase in activity observed was not due to an increase in the affinity of the enzyme for its substrate. The kinetic data were consistent with the theory of noncompetitive inhibition. 6. The activation of human amniotic fluid renin by pepsin may be caused by a change in the tertiary structure of the molecule subsequent to a proteolytic action that does not remove detectable polypeptide components.

Amniotic Fluid↗

PubMed1976

Pepsin-solubilized collagen of human nucleus pulposus and annulus fibrosus.

Human nucleus pulposus and annulus fibrosus, obtained at autopsy from patients 7-30 years of age, were extracted with 2 M guanidine-HCl (pH 5.82) to remove proteoglycans, then stirred with pepsin in 0.5 M acetic acid, followed by three 24-h extractions with 1 M NaCl (pH 7.5) and one 24-h extraction with 2 M KSCN (potassium thiocyanate) (pH 7.2). Pepsin and NaCl solubilized an average of about 30% of nucleus pulposus collagen and 18% of annulus fibrosus collagen. KSCN extracted a further 34% of nucleus pulposus collagen and only 4% of annulus fibrosus collagen. CM-cellulose chromatography of nucleus and annulus collagen purified from the pepsin, NaCl and KSCN supernatants consistently revealed only one peak, always appearing slightly ahead of the alpha1 position for rat tail tendon type I collagen. Polyacrylamide and SDS-gel electrophoresis consistently revealed only one band with the mobility of alpha1 chains. Amino acid composition of collagen from nucleus and annulus is comparable to those of mammalian and avian cartilage type II collagen, and distinctly different from those of rat tail tendonand guinea pig skin type I collagens. Periodate oxidation of nucleus and annulus collagens showed that 81% and 67%, respectively, of the hydroxylysine residues survive treatment, compared to 71% for bovine articular cartilage collagen and 17% for guinea pig skin collagen. Total hexose analysis revealed 1.8 muM and 2.0 muM hexose per muM periodate-stable hydroxylysine in nucleus and annulus collagens, respectively. Ion exchange chromatography showed the presence of glucose and galactose in a ratio of 0.92:1 in nucleas collagen and 1.07:1 in annulus collagen. Pepsin-solubilized, NaCl-extracted collagen from nucleus and annulus formed native-type fibrils in vitro. The banding patterns of ATP-induced segment-long-spacing precipitates of nucleus and annulus collagens were identical to each other and indistinguishable from those of cartilage (type II) collagen, but distinctly different from those of rat tail tendon (type I) collagen. These data suggest that the collagen which can be extracted after limited pepsin attack of human nucleus and annulus is of the form [alpha1 (II)]3.

Adolescent↗

PubMed1983

Determination of pepsin (EC 3.4.23.1) and gastricsin (EC 3.4.23.3) in gastric juice by rocket immunoelectrophoresis.

Antisera were raised in rabbits against chromatographically purified preparations of pepsin and gastricsin. With these antisera the contents of pepsin and gastricsin in gastric juice were determined by rocket immunoelectrophoresis. The potential content of pepsin and gastricsin of a secondary standard of gastric mucosal extract was calibrated against the chromatographically purified enzymes. This secondary standard was used for routine analyses. The intra-assay and between-assay precision was 3-4% and 6-9%, respectively. Ten healthy volunteers underwent a standard pentagastrin test. The amounts of pepsin and gastricsin determined by rocket immunoelectrophoresis corresponded to the amounts observed by ion exchange chromatography of gastric juice. After stimulation with pentagastrin the secretion of both pepsin and gastricsin was increased about 10 times.

Adult↗

PubMed1989

Role of arachidonic acid metabolites in acid-pepsin injury to rabbit esophagus.

The role of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in experimental esophageal were lumenally perfused for 1 h with acidified saline (pH 2.0) with or without pepsin followed by a second hour with acidified saline. Separate groups of pepsin-perfused animals were pretreated with indomethacin, a cyclooxygenase inhibitor, or BW755C, a lipoxygenase-cyclooxygenase inhibitor. Esophageal injury was graded grossly. H+ and hemoglobin fluxes were determined. Acidified saline caused no significant damage. Pepsin induced moderate injury. Indomethacin decreased pepsin-induced H+ flux by 55% without affecting the other indices. BW755C, by all measurements, dramatically increased pepsin-induced injury. In separate experiments, cyclooxygenase activity was decreased by indomethacin and BW755C by 62% and 49%, respectively. Lipoxygenase activity was decreased 74% by BW755C and was not significantly affected by indomethacin. These results suggest that esophageal cytoprotection is mediated by endogenous lipoxygenase metabolites.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1995

Ontogeny of human gastric lipase and pepsin activities.

BACKGROUND/AIMS: The developmental profile of human gastric lipase activity as well as the secretory capacity of the immature gastric mucosa are still unknown. The aims of this study were to establish tissue activity levels for lipase and pepsin in the various anatomical regions of the developing stomach and to assess whether lipase is secreted by the fetal gastric mucosa. METHODS: Lipase and pepsin activities were assayed in 49 specimens of different gestational ages. Gastric explants were cultured in chemically defined medium for up to 5 days, and enzymic activities were measured in tissues and in the culture media. RESULTS: Lipolytic activity was present in gastric tissues at 10-13 weeks and steadily increased for up to 20 weeks, whereas pepsin activity did not vary significantly over the periods of study. There was a clear decreasing gradient of lipase activity; the highest activity was in the fundic area, and the lowest activity was in the antrum. Quantitative pepsin activity did not vary over the gastric regions. During culture, total lipolytic and pepsin activity increased 3.8-fold, and both enzymes were secreted into the culture medium. CONCLUSIONS: Gastric lipase appears as early as 10-13 weeks. Adult distribution of the enzyme became established by 16 weeks' gestation. The secretion of lipase into the organ culture suggests that the gastric mucosa is the main source of lipolytic activity in gastric aspirates of premature infants.

Female↗

PubMed1984

Occupational asthma due to pepsin.

A 30-year-old atopic worker exposed to pepsin powder, herb, and pollen extracts at work developed an increase in asthmatic symptoms. Monitoring of peak expiratory flow rate revealed more important fluctuations at work. Skin prick tests yielded a large immediate reaction to pepsin. Specific inhalation challenges confirmed the diagnosis; an intense early response was documented after exposure to pepsin. The pepsin IgE RAST was positive and selectively inhibited by pepsin.

Adult↗

PubMed1983

Surprising consequences of the tendency of pepsin to catalyze condensation reactions between small peptides.

Pepsin catalyzes numerous acyl-transfer reactions. Are peptic acyl-enzyme intermediates involved in such reactions? To start, we examine the cleavage of Leu-Trp-Met-Arg at pH 3.4-4.5 in the presence of 25 mM tryptophanamide. Substantial amounts of Leu-TrpNH2 are generated. However, the appearance of this acyl-transfer product cannot be attributed to the intervention of Leu-pepsin and its trapping by tryptophanamide. Experiment proves that Leu-Trp-Met-Arg affords Leu3, which, in turn, reacts with tryptophanamide to produce Leu-TrpNH2. Both the formation of Leu3 from Leu-Trp-Met-Arg and the conversion of Leu3 + tryptophanamide into Leu-TrpNH2 can potentially implicate the generation and trapping of a Leu-pepsin intermediate. Does experiment support either possibility? The answer is no. Our data show that most of the Leu3 derived from Leu-Trp-Met-Arg stems from an autocatalytic condensation process whereby Leu3 already present speeds the conversion of the leucine residues of unreacted Leu-Trp-Met-Arg into more Leu3. Technical problems have prevented us from determining whether the first Leu3 formed results from the trapping of an acyl-enzyme intermediate. The generation of Leu-TrpNH2 from Leu3 was studied primarily via a more tractable analogous reaction: Leu-Trp-Leu + tryptophanamide leads to Leu-TrpNH2. The mechanism governing these transformations is highly complex. Its major feature is an initial condensation between two molecules of substrate. All the examples investigated further illustrate the marked tendency of pepsin to catalyze condensation reactions between suitably constructed small peptides. The prevalence of these reactions complicates the interpretation of much data bearing on pepsin's mechanism of action.

Amino Acid Sequence↗

PubMedDate not supplied

Control of pepsin secretion by regulatory peptides in the rat stomach: comparison with acid secretion.

Previous studies of the control of pepsin secretion by neurohumoral agents showed some discrepancies between in vitro (isolated cells) and in vivo experiments. In the present work, the effects on pepsin secretion of CCK, pentagastrin, secretin, VIP, neurotensin, histamine, and methacholine were reinvestigated in conscious gastric fistula rats, in comparison to acid secretion. ED50's and doses inducing maximal responses were measured to directly compare the potency and efficacy of these substances. Methacholine was the most efficient (maximal response = 4.5 x basal level, ED50 = 1.3 mumol/kg.h) and CCK the most potent (ED50 = 1.9 nmol/kg.h) stimulant, whereas secretin was a potent (ED50 regulators of pepsin secretion in the rat. Pentagastrin and histamine did not stimulate pepsin output, as found by others with isolated chief cells in vitro. Neurotensin and large doses of VIP marginally inhibited pepsin secretion.

Animals↗

PubMed2005

Effect of dimethyl sulphoxide on the crystal structure of porcine pepsin.

The structure of porcine pepsin crystallized in the presence of dimethyl sulphoxide has been analysed by X-ray crystallography to obtain insights into the structural events that occur at the onset of chemical denaturation of proteins. The results show that one dimethyl sulphoxide molecule occupies a site on the surface of pepsin interacting with two of its residues. An increase in the average temperature factor of pepsin in the presence of dimethyl sulphoxide has been observed indicating protein destabilization induced by the denaturant. Significant increase in the temperature factor and weakening of the electron density have been observed for the catalytic water molecule located between the active aspartates. The conformation of pepsin remains unchanged in the crystal structure. However, the enzyme assay and circular dichroism studies indicate that dimethyl sulphoxide causes a slight change in the secondary structure and complete loss of activity of pepsin in solution.

Animals↗

PubMed2005

Affinity chromatography of porcine pepsin A using quinolin-8-ol as ligand.

Stationary phase containing quinolin-8-ol immobilized on macroporous methacrylate support for the affinity chromatography of porcine pepsin A is described. Optimized chromatographic conditions for separation of porcine pepsin A on this stationary phase were found investigating the influence of pH, concentration, ionic strength and chemical composition of the used mobile phases. The stationary phase shows a good reproducibility of chromatographic analyses (relative standard deviation, +/-2%), a high recovery (ca. 93%) and a satisfactory capacity (13 mg pepsin A/1 mL stationary phase) for porcine pepsin A. The obtained findings confirm the applicability of affinity chromatography on the stationary phase with immobilized quinolin-8-ol to the isolation and determination of porcine pepsin A.

Animals↗