Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of omeprazole, a substituted benzimidazole, on gastric acid and pepsin secretion have been studied in twelve healthy subjects. From six to eight hours after a single oral dose of 30 mg, there was a 66% reduction in basal acid output, and a 71.2% reduction in pentagastrin stimulated acid output. A single dose of 60 mg produced a 91.7% reduction in basal acid output and a 95.3% reduction in pentagastrin stimulated acid output. After seven days treatment with 30 or 60 mg daily, there was almost 100% inhibition of both basal and pentagastrin stimulated acid output. Omeprazole did not significantly affect pepsin secretion which is in keeping with its proposed mode of action, as an inhibitor of the H+/K+-ATPase enzyme on the secretory membrane of the parietal cell. There were no side effects after omeprazole either with single or repeated dosing.
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PMID:Effects of single and repeated doses of omeprazole on gastric acid and pepsin secretion in man. 642 81

Omeprazole, a substituted benzimidazole, and a potent inhibitor of gastric parietal cell H+/K+ ATPase, was tested for drug interactions at two dose levels (30 mg and 60 mg/day) in man using the model drugs [14C]-aminopyrine and antipyrine. Elimination of both models was assessed before and after 15 days treatment with omeprazole. In addition [14C]-aminopyrine metabolism was assessed on day 2 of treatment to investigate the rapidity of onset of any effect. In 10 healthy male volunteers omeprazole 60 mg/day for 14 days prolonged aminopyrine 14CO2 half life (t1/2), measured on the 15th day, by 21% (P less than 0.05), and reduced percent dose demethylated in 2 h (ABT2) by 19% (P less than 0.005). No effect was seen on day 2 of therapy. After 14 days treatment antipyrine half-life was prolonged by 10% (P less than 0.025) and clearance was reduced by 14% (P = 0.063). In nine healthy male volunteers omeprazole 30 mg/day for 14 days prolonged aminopyrine 14CO2 by 13% and reduced ABT2 by 11%. Both changes just failed to reach statistical significance. At this dose antipyrine metabolism was unaltered. As the dose of omeprazole used in clinical practice may be less than 30 mg/day it is unlikely that metabolic inhibition will occur during routine use, although it will be necessary to test for interactions with therapeutically more important compounds. Interactions should be looked for when large doses of omeprazole are being used to treat hypersecretory states.
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PMID:Omeprazole: effects on oxidative drug metabolism. 648 57

Omeprazole is a potent inhibitor of gastric acid secretion (GAS). It has a unique mechanism of action within the parietal cell where it inhibits (H+-K+) ATPase in secretory membranes. The inhibitory effect of omeprazole was measured over a 24-hr period in the dog. Seventy-five minutes after start of pentagastrin-stimulated GAS, placebo or omeprazole (0.5-3.0 micrograms/kg) iv was given to six dogs and GAS was collected for another 2 hr. Twenty-four hours later, GAS was again measured. Omeprazole produced a prompt and dose-dependent reduction of GAS, and significant suppression (44%) was still present at 24 hr.
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PMID:Omeprazole, a long-lasting inhibitor of gastric secretion. 672 28

Omeprazole and other substituted benzimidazoles produce a marked inhibition of gastric acid secretion with a long duration of action. Any kind of stimulated acid secretion is inhibited by the substituted benzimidazoles. The inhibitory mechanism of action is very selective. The substituted benzimidazoles inhibit the parietal cell H+, K+-ATPase, an enzyme which is the proton pump in the secretory membrane of the parietal cell. An oral daily dose of 15 mg omeprazole in humans produced about 80% acid inhibition just after dosage and about 40% 24 hours later. Preliminary results in duodenal ulcer patients show that a daily dose of 20-60 mg omeprazole produces fast ulcer healing in almost all patients.
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PMID:[Acid secretion inhibition with new mechanisms of action: substituted benzimidazole]. 674 Feb 86

Peripheral regulation of gastric acid secretion is initiated by the release of gastrin from the G cell. Gastrin then stimulates the cholecystokinin-B receptor on the enterochromaffin-like cell beginning a calcium signaling cascade. An exocytotic release of histamine follows with concomitant activation of a C1- current. The released histamine begins the H2-receptor mediated sequence of events in the parietal cell, which results in activation of the gastric H+/K+ - ATPase. This enzyme is the final common pathway of acid secretion. The H+/K+ - ATPase is composed of two subunits: the larger alpha-subunit couples ion transport to hydrolysis of ATP, the smaller beta-subunit is required for appropriate assembly of the holoenzyme. Both the membrane and extracytoplasmic domain contain the ion transport pathway, and therefore, this region is the target for the antisecretory drugs of the post-H2 era. The 100 kDa alpha-subunit has probably 10 membrane spanning segments with, therefore, five extracytoplasmic loops. The 35 kDA beta-subunit has a single membrane spanning segment, and most of this protein is extracytoplasmic with the six or seven N glycosylation consensus sequences occupied. Omeprazole is an acid-accumulated, acid-activated, prodrug that binds covalently to two cysteine residues at positions 813 (or 822) and 892, accessible from the acidic face of the pump. Lansoprazole binds to cys321, 813 (or 822) and 892; pantoprazole binds to cys813 and 822. The common binding site for these drugs (cys813 or 822) is responsible for the inhibition of acid transport. Covalent inhibition of the acid pump improves control of acid secretion, but since the effective half life of the inhibition in man is about 48 hr, full inhibition of acid secretion, perhaps necessary for eradication of Helicobacter pylori in combination with a single antibiotic, will require prolongation of the effect of this class of drug.
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PMID:Gastric acid secretion: activation and inhibition. 750 35

The yeast plasma membrane proton pumping ATPase (H(+)-ATPase) was investigated as a potential molecular target for antifungal drug therapy by examining the inhibitory effects of the sulfhydryl-reactive reagent omeprazole on cell growth, glucose-induced medium acidification and H(+)-ATPase activity. Omeprazole inhibits the growth of Saccharomyces cerevisiae and the human pathogenic yeast Candida albicans in a pH dependent manner. Omeprazole action is closely correlated with inhibition of the H(+)-ATPase and is fungicidal. Glucose-dependent medium acidification is correspondingly blocked by omeprazole and appears to require the H(+)-ATPase to proceed through its reaction cycle. A strong correlation is observed between inhibition of medium acidification and H(+)-ATPase activity in plasma membranes isolated from treated cells. The inhibitory properties of omeprazole are blocked by pre-treatment of activated drug with beta-mercaptoethanol, which is consistent with the expected formation of a sulfhydryl-reactive sulfenamide derivative. Mutagenesis of the three putative membrane sector cysteine residues (C148S, C312S, C867A) in the S. cerevisiae H(+)-ATPase suggests that covalent modification of the conserved C148 residue may be important for inhibition of ATPase activity and cell growth. Other mutations (M128C and G158D/G156C) mapping near C148 support the importance of this region by modulating omeprazole inhibition of the H(+)-ATPase. These findings suggest that the plasma membrane H(+)-ATPase may serve as an important molecular target for antifungal intervention.
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PMID:The yeast plasma membrane proton pumping ATPase is a viable antifungal target. I. Effects of the cysteine-modifying reagent omeprazole. 754 48

1. Omeprazole, an antiulcer drug, inhibits the gastric acid pump via blocking the parietal cell (H+ + K+)-ATPase. Omeprazole was also reported to have an inhibitory action on polymorphonuclear neutrophil activities. In the present study the potential effect of omeprazole on human natural killer cell (NK) activity was investigated. 2. Omeprazole decreased NK cytotoxic activity in a dose-dependent manner. 3. Degraded omeprazole showed a similar action. 4. In vitro NK inhibitory action of omeprazole and its acid-degraded form was observed at the concentrations equal and higher than 18 microM (micromolar). 5. NK inhibitory action of omeprazole was recovered to 75% by washing away of the agent. 6. Omeprazole decreased the conjugate formation of effector and target cells by 50% at the concentration of 288 microM
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PMID:The effect of omeprazole on human natural killer cell activity. 759 Jan 40

The gastric H+,K+ ATPase--the gastric acid pump--is the molecular target for the class of antisecretory drugs called the proton-pump inhibitors (PPIs). These compounds--omeprazole, lansoprazole, and pantoprazole--contain, as their core structure, 2-pyridyl methylsulfinyl benzimidazole. The H+,K+ ATPase is a heterodimer composed of a 1034-amino acid catalytic alpha peptide and a glycosylated 291-amino acid beta subunit. The alpha subunit probably contains 10 membrane-spanning sequences; the beta, a single transmembrane segment. The PPIs have a pKa of about 4.0; hence they accumulate only in the acidic secretory canaliculus of the stimulated parietal cell. Here they undergo conversion to a cationic sulfenamide, which then reacts with available cysteines on the extracytoplasmic face of the alpha subunit. Omeprazole reacts and forms disulfide bonds with cys813(822) and cys892; lansoprazole, with cys813(822), cys892, and cys321; and pantoprazole, with cys813 and -822. The antisecretory effect of the drugs reflects their short plasma half-life (approximately 60 min), the number of active pumps during that time, and the recovery of pumps following biosynthesis and reversal of inhibition. These drugs also show synergism with either amoxicillin or clari- thromycin in eradicating Helicobacter pylori, an organism shown to be important in duodenal and gastric ulcer disease. Their action is probably due to elevation of pH in the environment of the organism, rather than to any direct action.
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PMID:The pharmacology of the gastric acid pump: the H+,K+ ATPase. 759 95

The effects of gastric secretagogues, and other agents that modify H+,K(+)-ATPase activity and cell calcium concentration, on the rate of oxoglutarate oxidation were investigated in isolated gastric glands. Oxoglutarate was oxidized in a dose-dependent manner by gastric glands, with an apparent Km for oxoglutarate of 3.9 +/- 0.5 mM. Oxoglutarate progressively inhibited the rate of glucose oxidation. In the presence of 0.5 mM oxoglutarate plus 10 mM glucose, the latter substrate was preferentially oxidized and contributed most to oxygen uptake. With 10 mM oxoglutarate plus 10 mM glucose, the rate of glucose oxidation was greatly inhibited and oxoglutarate oxidation accounted for most of the oxygen consumption. Acid secretion (aminopyrine accumulation) was significantly increased by 0.1 mM histamine in glands oxidizing 10 mM oxoglutarate, although this stimulation was significantly lower than that observed in the presence of 0.5 mM oxoglutarate plus 10 mM glucose. Omeprazole, an inhibitor of the H+,K(+)-ATPase, significantly reduced the oxidation of oxoglutarate, whereas NH4+, an activator of the enzyme, stimulated the oxidation of a submaximal dose of oxoglutarate. Carbachol at 0.1 mM significantly increased the rate of oxidation of non-saturating concentrations of oxoglutarate. The calcium ionophore ionomycin at 10 microM produced a similar effect. Chelation of intracellular calcium by BAPTA AM caused a significant inhibition of oxoglutarate oxidation. The results provide further evidence that changes in the ATP:ADP ratio resulting from activation of the H+,K(+)-ATPase, and calcium ions are involved in the mechanisms of activation of oxidative metabolism in the parietal cell.
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PMID:Interactions between oxoglutarate oxidation and acid secretion in isolated rabbit gastric glands. 764 8

1. Cimetidine was more potent 4 hr after a single injection of 25 or 100 mg/kg body wt in increasing gastric pH than other H2 receptor antagonists, ranitidine and famotidine but was less efficient than H+/K(+)-ATPase inhibitors. Omeprazole rose proventricular and gizzard pH at a lower dose than SCH 28080 and Ro 18-5364 (30, 50 and 200 mg/kg body wt, respectively). 2. Proventricular and gizzard pH values were maximal 1 and 4 hr after a single injection of 7.5 mumol/kg body wt omeprazole. Inhibition of acid secretion was maintained for 24 hr after an injection of 100 mumol/kg. 3. H+/K(+)-ATPase activity in vitro was 10 mumol Pi/hr/mg protein in the microsomal fractions of the proventriculus. It was doubled by nigericine and inhibited by SCH 28080. However, western blots by high specific H+/K(+)-ATPase monoclonal antibody 95-A3 and 95-111 recognized a 42 kDa band but hardly exhibited the specific 95 kDa band recognition. 4. Chickens and immature pullets showed a higher H+/K(+)-ATPase activity than laying hens. Calcium level of the diet did not affect the enzyme activity but coarse particles of calcium fed to pullets or laying hens enhanced the H+/K(+)-ATPase activity when compared with ground particles.
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PMID:Gastric acid secretion in the chicken: effect of histamine H2 antagonists and H+/K(+)-ATPase inhibitors on gastro-intestinal pH and of sexual maturity calcium carbonate level and particle size on proventricular H+/K+ ATPase activity. 790 2


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