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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of the flavonoids flavone, flavanone and quercetin on parietal cell acid production, H+/K(+)-ATPase activity, gastric mucosal prostaglandin E2 biosynthesis and Helicobacter pylori growth was studied. All flavonoids inhibited acid production in isolated parietal cells in response to histamine and dibutyryl-cAMP stimulation (IC50 values between 26 and 139 mumol/l) and inhibited H+/K(+)-ATPase activity. Inhibition of H+/K(+)-ATPase activity was dependent on the ATP concentration. Fluorescence measurements showed that flavanone reacts with ATP. These findings indicate that the inhibitory action of flavonoids on H+/K(+)-ATPase activity is related to their ability to complex ATP. Flavone and flavanone (10 and 100 mumol/l) stimulated prostaglandin E2 production in isolated gastric mucosal cells. Furthermore, the compounds inhibited Helicobacter pylori growth in a concentration-dependent manner. From these finding it appears that flavonoids are a group of compounds which could have a therapeutic potential for treatment of gastrointestinal diseases associated with Helicobacter pylori infection.
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PMID:Effects of flavonoids on parietal cell acid secretion, gastric mucosal prostaglandin production and Helicobacter pylori growth. 764 73

The pharmacology, pharmacokinetics, efficacy, safety, and dosage and administration of lansoprazole and omeprazole are reviewed. Lansoprazole and omeprazole are proton-pump inhibitors (PPIs). These agents bind covalently to hydrogen/potassium-exchanging adenosine triphosphatase in gastric parietal cells, rendering the molecule nonfunctional and inhibiting the secretion of gastric acid. The bioavailability of lansoprazole is 85%; that of omeprazole is 54%. Although lansoprazole and omeprazole have a plasma half-life of less than 2 hours, the duration of action is more than 24 hours. Clinical trials have shown lansoprazole and omeprazole to be effective in the treatment of duodenal ulcers, gastric ulcers, peptic ulcer disease involving Helicobacter pylori infection, recurrent ulcers, ulcers induced by nonsteroidal anti-inflammatory drugs, reflux esophagitis, Barrett esophagus, and Zollinger-Ellison syndrome. In many cases, these PPIs were more effective than histamine H2-receptor antagonists or worked when the latter failed. Lansoprazole and omeprazole have similar adverse-effect profiles and are well tolerated in both long- and short-term therapy. The dosage and duration of therapy vary with the condition being treated or the individual patient. Dosage adjustments should be considered only in the case of lansoprazole in patients with severe liver disease. Lansoprazole and omeprazole are highly specific in blocking a critical step in gastric acid production and have been found to be safe and effective in the treatment of many acid peptic disorders.
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PMID:Lansoprazole and omeprazole in the treatment of acid peptic disorders. 895 52

Patients with acid-related diseases often need to take multiple medications. Treatment of Helicobacter pylori infection often includes either a histamine type 2 (H2)-receptor antagonist or a proton pump (H+,K(+)-ATPase) inhibitor (proton pump inhibitor), administered in conjunction with one or more antimicrobials. Also, treatment for acid-related diseases often requires extended therapy during which many concomitant medications may be administered for concurrent disease states. Polypharmacy may be the result, particularly in elderly patients, who are at increased risk for both acid-related and many other diseases. Thus, it is important to understand the potential for clinically significant drug-drug interactions in this setting. H2-receptor antagonists and proton pump inhibitors can influence the pharmacokinetic profiles of other commonly administered medications by elevating intragastric pH, which can alter drug absorption, and by interacting with the cytochrome P (CYP) 450 enzyme system, which can affect drug metabolism and clearance. Such interactions are particularly important when they affect the pharmacokinetics of drugs with narrow therapeutic ranges (e.g. warfarin, digoxin). In these cases, drug-drug interactions can result in significant toxicity and even death. There are marked differences among H2-receptor antagonists and proton pump inhibitors in their potential for such interactions. The oldest drugs in each class, cimetidine and omeprazole, respectively, have the greatest potential to alter CYP activity and change the pharmacokinetics of other drugs. The most recently developed H2-receptor antagonist, famotidine, and the newer proton pump inhibitors, rabeprazole and pantoprazole, are much less likely to induce or inhibit CYP and thereby change the metabolism of other medications. These differences are important when choosing medications for the safe treatment of patients with acid-related diseases.
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PMID:Review article: drug interactions with agents used to treat acid-related diseases. 1049 25

Clinical studies and in vitro data from isolated parietal cells suggest that acute Helicobacter pylori infection inhibits acid secretion. Gastric acidification is mediated by H(+)-K(+)-ATPase, an integral protein of parietal cell apical membranes. To test the hypothesis that H. pylori downregulates H(+)-K(+)-ATPase alpha-subunit (HKalpha) gene expression and to identify potential intracellular signaling pathways mediating such regulation, we transfected human gastric adenocarcinoma (AGS) cells with human and rat HKalpha 5'-flanking DNA fused to a luciferase reporter plasmid. Histamine caused dose-dependent, cimetidine-sensitive (10(-4) M) increases in cAMP, free intracellular Ca(2+), and HKalpha promoter activation in AGS cells. H. pylori infection of transfected AGS cells dose dependently inhibited basal and histamine-stimulated HKalpha promoter activity by 80% and 66%, respectively. H. pylori dose dependently inhibited phorbol myristate acetate-induced (10(-7) M) and staurosporine- (10(-7) M) and calphostin C-sensitive (5 x 10(-8) M) activation of HKalpha promoter. Also, H. pylori inhibited epidermal growth factor (EGF) (10(-8) M), genistein-sensitive (5 x 10(-5) M) activation of HKalpha promoter, reducing activity to 60% of basal level. These data suggest that H. pylori inhibits HKalpha gene expression via intracellular pathways involving protein kinases A and C and protein tyrosine kinase, AGS cells have functional histamine H(2) and EGF receptors, and transiently transfected AGS cells are a useful model for studying regulation of HKalpha gene expression.
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PMID:Inhibition of human gastric H(+)-K(+)-ATPase alpha-subunit gene expression by Helicobacter pylori. 1085 29

Helicobacter pylori infection is a causal factor of gastric cancer (which is associated with low gastric acid secretion) or duodenal ulcer (high acid secretion). Parietal cells and ECL cells in the stomach are controlled by gastrin, which plays a crucial role in the regulation of acid secretion. The present study was undertaken to identify a possible role of gastrin in determining the different responses of the parietal cells and ECL cells to chronic H. pylori infection. Wild-type (C57BL/6J) gastrin(+/+) mice and gastrin(-/-) knockout mice, generated through targeted gene disruption and backcrossed eight times to C57BL/6J, were infected with H. pylori for 9 months. The acid output was measured 4 h after pylorus ligation (known to cause vagal excitation). The gastric mucosa was examined by immunocytochemistry with antisera to alpha-subunit of H+/K(+)-ATPase for the parietal cells, and to histamine and vesicle monoamine transporter-2 for the ECL cells, and by quantitative electron microscopy. In infected gastrin(+/+) mice, the acid output and the percentage of secreting parietal cells (freely fed state) were 20-30% of the values in uninfected controls, while the density and ultrastructure of parietal cells were normal. The infected mice had hypergastrinemia and displayed hypertrophy and hyperplasia of ECL cells. Although uninfected gastrin(-/-) mice had lower the acid output than uninfected gastrin(+/+) mice, there was a higher acid output (approximately 3 times) in infected gastrin(-/-) mice than their uninfected homologues. The numbers of parietal cells and ECL cells remained unchanged in infected gastrin(-/-) mice. In conclusion, chronic H. pylori infection results to impaired parietal-cell function (acid hyposecretion), hypergastrinemia and hyperplasia of ECL cells in wild-type mice but leads to vagally induced hypersecretion in gastrin-deficient mice.
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PMID:Chronic Helicobacter pylori infection results in gastric hypoacidity and hypergastrinemia in wild-type mice but vagally induced hypersecretion in gastrin-deficient mice. 1455 57

Host specific T-cell response is critical for the outcome of Helicobacter pylori infection. In genetically susceptible individuals, H. pylori can activate gastric CD4+ Th1 cells that recognize cross-reactive epitopes shared by H. pylori proteins and self H+, K+-ATPase, leading to gastric autoimmunity via molecular mimicry.
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PMID:Helicobacter pylori and gastric autoimmunity. 1559 26

Chronic gastritis, or chronic inflammation in gastric antral and/or corpus mucosa, is a common pathological condition affecting over half the general population. Progression of chronic gastritis from Helicobacter pylori infection to severe gastric mucosal atrophy usually takes decades and varies considerably from person to person. Therefore, studies of clinically selected material cannot provide a complete picture of natural evolution of the disease or its wide variability. An overview of immunological and morphological aspects of chronic gastritis in an epidemiological context, based on data from the literature and the author's studies, reveal dynamic interaction between H. pylori infection and host response to the organism's antigens, and to gastric autoantigens including gastric H+K+ ATPase. Further population and followup studies of antral and corpus gastritis at different stages of evolution are needed, in combination with new methods, to elucidate further the roles of infection, and gastric-antrum- and corpus-mucosa-related autoimmune responses, in the pathogenesis of chronic gastritis.
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PMID:Contribution of epidemiological studies to gastritis immunology. 1576 88

Helicobacter pylori infection is the major cause of gastroduodenal pathologies, but only a minority of infected patients develop chronic and life threatening diseases, as peptic ulcer, gastric cancer, B-cell lymphoma, or autoimmune gastritis. The type of host immune response against H. pylori is crucial for the outcome of the infection. A predominant H. pylori-specific Th1 response, characterized by high IFN-gamma, TNF-alpha, and IL-12 production associates with peptic ulcer, whereas combined secretion of both Th1 and Th2 cytokines are present in uncomplicated gastritis. Gastric T cells from MALT lymphoma exhibit abnormal help for autologous B-cell proliferation and reduced perforin- and Fas-Fas ligand-mediated killing of B cells. In H. pylori-infected patients with autoimmune gastritis cytolytic T cells infiltrating the gastric mucosa cross-recognize different epitopes of H. pylori proteins and H+K+ ATPase autoantigen. These data suggest that peptic ulcer can be regarded as a Th1-driven immunopathological response to some H. pylori antigens, whereas deregulated and exhaustive H. pylori-induced T cell-dependent B-cell activation can support the onset of low-grade B-cell lymphoma. Alternatively, H. pylori infection may lead in some individuals to gastric autoimmunity via molecular mimicry.
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PMID:Helicobacter pylori, T cells and cytokines: the "dangerous liaisons". 1586 4

Proton pump inhibitors have become one of the cornerstones in the treatment of Helicobacter pylori infection. Rabeprazole (Pariet) is a substituted benzimidazole proton pump inhibitor with potent gastric acid suppression properties. Its high acid-base dissociation constant allows activation over a broader pH range, resulting in quick, irreversible binding to the H+/K+-ATPase pump, and a more rapid onset of action compared with omeprazole, lansoprazole and pantoprazole. Unlike other proton pump inhibitors, the metabolism of rabeprazole is primarily via a nonenzymatic reduction to the thioether derivative, and the cytochrome P450 isoenzyme 2C19 is only partly involved in its metabolism. The effect of genetic polymorphism in cytochrome P450 isoenzyme 2C19 on the pharmacokinetics and pharmacodynamics of rabeprazole is therefore limited. In humans, once-daily dosing of 5-40 mg of rabeprazole inhibits gastric acid secretion in a dose-dependent manner. In vitro studies have shown that rabeprazole possesses more potent antibacterial properties against the growth of H. pylori than other proton pump inhibitors. Furthermore, its thioether derivative has more potent inhibitory in vitro activity against the growth and motility of clarithromycin-resistant H. pylori than other proton pump inhibitors or commonly used antimicrobials. Despite these inherent favorable characteristics of rabeprazole, randomized controlled trials have largely shown equivalence amongst proton pump inhibitors when used with two antibiotics in the eradication of H. pylori, with cure rates of 75-89% on an intent-to-treat basis. However, rabeprazole appears to consistently achieve such comparable eradication rates even when used at reduced doses (10 mg twice daily) as part of clarithromycin-based triple therapy.
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PMID:Rabeprazole: the role of proton pump inhibitors in Helicobacter pylori eradication. 1630 99

Eradication of Helicobacter pylori infection leads to recovery of gastric acid secretion in some individuals but the mechanism is not fully understood. In the short term, there is an impressive increase in expression of H+/K+-ATPase pumps without an increase in the number of parietal cells. Longer follow up studies are needed to see if the parietal cell mass eventually recovers.
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PMID:Mechanisms of increased acid secretion after eradication of Helicobacter pylori infection. 1587


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