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:1.6.99.6 (NADPH oxidase)
10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have restudied two kindreds that formed the basis of the original report of autosomal recessive chronic granulomatous disease (CGD) associated with leukocyte glutathione peroxidase deficiency. Case 1 from the original study and the surviving brother of the originally reported case 2 both have severe CGD, with no detectable respiratory burst activity in purified intact neutrophils. However, their leukocytes exhibit normal glutathione peroxidase enzyme activity and gene expression. Examination of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase components known to be defective in CGD reveals no detectable cytochrome b558 nor any membrane activity in a cell-free NADPH oxidase assay system. Molecular analysis of the genes encoding cytochrome b558 subunits shows, in case 1, a C-->T substitution at nucleotide 688 of the gene encoding the gp91-phox subunit of cytochrome b558, resulting in a termination signal in place of Arginine-226. Levels of gp91-phox mRNA are markedly decreased despite normal levels of gene transcription, indicating a post-transcriptional effect of the nonsense mutation on mRNA processing or stability. The X-linked form of CGD developed in this cytogenetically normal female due to the uniform inactivation of the normal X chromosome in her granulocytes, indicated by the expression in her granulocyte mRNA of only one allele of a glucose-6-phosphate dehydrogenase polymorphisms for which she is heterozygous in genomic DNA. Case 2 (of the present study) has distinct mutations in each allele of the p22-phox gene.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chronic granulomatous disease and glutathione peroxidase deficiency, revisited. 794 43

The respiratory burst reaction, estimated as O2.- production, has been studied in rat peritoneal macrophages of different age (3, 12 and 24 months). To stimulate NADPH oxidase, the enzyme responsible for the respiratory burst, various stimuli that act in different ways have been used: PMA (phorbol myristate acetate), Con-A (concanavalin A) and N-FMLP (N-formyl-methionyl-leucyl-phenylalanine). All produced a decrease in response with age, with that from PMA being the greatest. The PMA-induced decrease in the O2.- production may be related to the inactivation of NADPH-producing enzymes such as glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase that we have found with age. Glutathione reductase, an enzyme that participates in the maintenance of the redox status in the cell, also showed an age-related decrease. Enzymes that participate in oxygen species scavenging, such as glutathione peroxidase and Cu/Zn superoxide dismutase, did not change with age, although an age-related decrease in catalase activity was found.
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PMID:Respiratory burst reaction changes with age in rat peritoneal macrophages. 821 68

1. The effect of lithium on phagocytic activity of polymorphonuclear leucocytes (PMNL) has been investigated by measurements of glucose-6-phosphate dehydrogenase (G6PD), NADPH oxidase and myeloperoxidase (MPO) both in lithium treated rats and lithium treated infected rats. 2. The results have been compared with two control groups, one of which was without lithium treatment and the other was only infected. 3. In the first experimental group increased activities of these enzymes have been observed, while in lithium-treated infected rats there was a decrease in the activities of the same three enzymes. 4. It is proposed that defense mechanisms against infection fail during the lithium treatment.
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PMID:Biochemical investigation of leukocyte functions during lithium therapy. 822 62

The bactericidal activity of neutrophils depends primarily on free oxygen radicals released by the activation of NADPH oxidase when neutrophils are stimulated by microorganisms. Severe glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with decreased NADPH production. Increased susceptibility to recurrent bacterial infections in children with severe neutrophil G6PD deficiency as a consequence of decreased NADPH production has been reported earlier. In this study, the in vitro activity of neutrophils from normal and G6PD-deficient individuals was assessed by measuring the [14C]CO2 released via the hexose monophosphate shunt from radiolabeled [1-14C]-glucose and the nitroblue tetrazolium (NBT) dye reduction test. Our results show that the G6PD activity of neutrophils from 48 individuals, identified as severely erythrocyte (RBC) G6PD deficient (< 2 U/10(12) RBC) was 23% of the enzyme activity of neutrophils from 53 individuals with normal RBC G6PD levels (98.8 U/10(12) RBC). However, the results of functional assays of neutrophils as measured by hexose monophosphate shunt and the NBT test were comparable in G6PD-deficient and normal individuals, suggesting that a reduced activity of G6PD to as low as 23% of normal does not affect neutrophil function.
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PMID:Effect of glucose-6-phosphate dehydrogenase deficiency on neutrophil function. 915 63

During the innate immune response, excessive release of reactive oxygen species (ROS) from sequestered phagocytes and activated resident macrophages represents the predominant component of oxidative stress in the liver and other tissues. The consequence of oxidative stress is determined by the status and adaptive changes of antioxidant pathways. In this review, we present evidence that the synchronized response of hepatic sinusoidal endothelial cells, the primary sites of phagocyte attachment, plays an important role in defense against phagocyte-derived ROS. An essential component of the metabolic adaptation of hepatic sinusoidal cells to lipopolysaccharide (LPS)-induced oxidative stress is the stimulated expression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the pentose cycle (hexose monophosphate shunt, HMS). All major ROS-metabolic enzymes, i.e., glutathione peroxidase, glutathione reductase, catalase, superoxide dismutases, NADPH oxidase, and nitric oxide synthase, directly or indirectly depend on NADPH, which is produced in the HMS in these cells. The functional significance of up-regulated HMS within a particular cell type depends on the accompanying adaptive changes in ROS-metabolizing enzymes. In LPS-activated Kupffer cells, the elevated expression of glucose transporter GLUT1 and G6PD mainly serves primed production of superoxide anion, hydrogen peroxide, and nitric oxide. In sinusoidal endothelial cells, the LPS-induced response pattern of glucose- and ROS-metabolizing enzymes results in elevated ROS detoxifying capacity. The described studies also suggest the existence of an intercellular oxidant balance between pro-oxidant Kupffer cells and antioxidant endothelial cells in the hepatic micro-environment. Maintenance of the intercellular oxidant/antioxidant balance between phagocytes and endothelial cells may represent an important mechanism protecting the hepatic parenchyma against exogenous oxidative stress during the inflammatory response.
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PMID:Endotoxemia, pentose cycle, and the oxidant/antioxidant balance in the hepatic sinusoid. 958 96

Since the generation of superoxide and hydrogen peroxide by NADPH oxidase and nitric oxide (NO) by NO synthase (NOS) in granulocytes is NADPH-dependent, we investigated the production of NO, superoxide and H2O2 in glucose 6-phosphate dehydrogenase (G6PD)-deficient human granulocytes. Our results showed that upon stimulation with either 5 microg/ml of lipopolysaccharide (LPS) or 10 microM of phorbol 12-myristate 13-acetate (PMA), the production of nitrite in normal granulocytes was elevated, 252 +/- 135% and 239 +/- 72%, respectively, compared to the resting stage. In contrast, G6PD-deficient granulocytes did not produce more nitrite upon stimulation with either LPS or PMA compared to the resting stage. Western blot analysis indicated a normal expression pattern of inducible NOS in G6PD-deficient granulocytes. In addition, the production of H2O2 and superoxide was also significantly impaired in G6PD-deficient granulocytes compared to control cells. These data demonstrate that G6PD deficiency causes an impairment in the production of NO, superoxide and H2O2.
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PMID:Impaired production of nitric oxide, superoxide, and hydrogen peroxide in glucose 6-phosphate-dehydrogenase-deficient granulocytes. 980 Nov 59

Lindane administration to rats (60 mg/kg b.w.) led to an enhancement in the oxidative stress status of the liver at 4 h after treatment, characterized by increases in hepatic thiobarbituric acid reactants (TBARS) formation and chemiluminescence, reduced glutathione (GSH) depletion, and diminution in the biliary content and release of GSH. These changes were observed in the absence of changes in either microsomal functions (cytochrome P450 content, NADPH-dependent superoxide radical production, and NADPH-cytochrome P450 reductase or NADPH oxidase activities) or in oxidative stress-related enzymatic activities (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and glutathione-S-transferases), over control values. Phenobarbital (PB) administration (0.1% in drinking water; 15 days) elicited an enhancement in liver microsomal functions, lipid peroxidation, and GSH content, without changes in oxidative stress-related enzymatic activities, except for the elevation in those of glutathione reductase and glutathione-S-transferase, compared to control rats. Lindane given to PB-pretreated rats did not alter liver microsomal functions, lipid peroxidation, glutathione status, or oxidative stress-related enzymatic activities, as compared to PB-pretreated animals. In addition, lindane induced periportal necrosis with hemorrhagic foci in untreated rats, but not in PB-pretreated animals. It is concluded that the early oxidative stress response of the liver to lindane and hepatic injury are suppressed by PB pretreatment via induction of microsomal enzymes in all zones of the hepatic acinus. reserved.
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PMID:Prolonged phenobarbital pretreatment abolishes the early oxidative stress component induced in the liver by acute lindane intoxication. 1081 30

The O2*(-) production has been studied in rat peritoneal neutrophils of different age (3, 12 and 24 months), in order to analyse whether the neutrophil respiratory burst is modified with increasing age. To stimulate NADPH oxidase, the enzyme responsible for the respiratory burst, two stimuli that act in different way have been used: phorbol myristate acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine (N-FMLP). Production of O2*(-) decreased with age in neutrophils stimulated with N-FMLP (about 40%), but not in the stimulated with PMA. No difference in NADPH oxidase activity was found with age. The NADPH is supplied to the respiratory burst mainly by the pentose phosphate shunt. A progressive and significant decrease in the two most important enzymes of this route, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, was detected as a function of age; in spite of this reduction, the NADPH produced by cells from old animals seems not limiting for the O2*(-) production. The N-FMLP-induced decrease in the O2*(-) production may be related to the age-dependent increase in the membrane fluidity observed. A decline in the cholesterol/phospholipid ratio and a rise in the total polyunsaturated fatty acids content were found, that correlated well with the increase in the membrane fluidity. The decrease (50%) of phosphatidylinositols in the 24-month-old animals may be also related to the age-impairment in the respiratory burst found after stimulation with N-FMLP. These studies suggest that the age-related alterations in neutrophil may result in diminished neutrophil function and increased susceptibility to infection in the ageing.
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PMID:Age-related changes in membrane lipid composition, fluidity and respiratory burst in rat peritoneal neutrophils. 1135 47

Though various tissue macrophages possess high glucose-6-phosphate dehydrogenase (G6PD) activity, which plays an important role in their phagocytosis/bactericidal function, the presence of this enzyme in human placental villous macrophages (Hofbauer cells) has not been determined. We examined the ultrastructural localization of glucose-6-phosphate dehydrogenase (G6PD) in Hofbauer cells in first and second trimester placental villi, using a newly developed enzyme-cytochemistry (copper-ferrocyanide) method. Electron-dense deposits indicative of G6PD activity were clearly visible in the cytoplasm and on the cytosolic side of the endoplasmic reticulum of Hofbauer cells. Positive and negative cytochemical controls ensured specific detection of enzyme activity. These observations indicated that Hofbauer cells abundantly possessed enzyme-cytochemically detectable G6PD activity. Hofbauer cell G6PD may play a role in placental defense, by supplying NADPH-dependent enzymes (i.e. nitric oxide synthase or NADPH oxidase) with NADPH. This enzyme may also fuel Hofbauer cells with ribose 5-phosphate during their cell proliferation and cell division.
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PMID:Enzyme-cytochemically detectable glucose-6-phosphate dehydrogenase in human villous macrophages (Hofbauer cells). 1171 77

The cytotoxicity of asbestos has been related to its ability to increase the production of reactive oxygen species (ROS), via the iron-catalyzed reduction of oxygen and/or the activation of NADPH oxidase. The pentose phosphate pathway (PPP) is generally activated by the cell exposure to oxidant molecules. Contrary to our expectations, asbestos (crocidolite) fibers caused a dose- and time-dependent inhibition of PPP and decreased its activation by an oxidative stress in human lung epithelial cells A549. In parallel, the intracellular activity of the PPP rate-limiting enzyme, glucose 6-phosphate dehydrogenase (G6PD), was significantly diminished by crocidolite exposure. This inhibition was selective, as the activity of other PPP and glycolysis enzymes was not modified, and was not attributable to a decreased expression of G6PD. On the opposite, the incubation with glass fibers MMVF10 did not modify PPP and G6PD activity. PPP and G6PD inhibition did not correlate with the increased nitric oxide (NO) production elicited by crocidolite in A549 cells. Experiments with the purified enzyme suggest that crocidolite inhibits G6PD by directly interacting with the protein. We propose here a new mechanism of asbestos-evoked oxidative stress, wherein fibers increase the intracellular ROS levels also by inhibiting the main antioxidant pathway of the cell.
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PMID:Crocidolite asbestos inhibits pentose phosphate oxidative pathway and glucose 6-phosphate dehydrogenase activity in human lung epithelial cells. 1197 96


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