Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure to hyperoxia causes loss of alveolar macrophage cell function. Toxicity was measured as suppression of the respiratory burst stimulated by phorbol myristate acetate subsequent to exposure (43.5% depression by 2-h exposure to 5 atm absolute O2 vs. controls). The presence of extracellular glutathione significantly protected these cells (7% loss). gamma-Glutamyl transpeptidase, a membrane enzyme with its active site directed outward, was necessary for use of extracellular glutathione. This was demonstrated using the gamma-glutamyl transpeptidase inhibitor, serine-borate complex, which significantly blocked both protection of cells by extracellular glutathione and extracellular glutathione-dependent synthesis of glutathione. The principal use of glutathione in antioxidant defense is as a substrate for glutathione peroxidase. The apparent Km for glutathione of glutathione peroxidase of rat alveolar macrophages was determined to be 2 mM; however, rat alveolar macrophages have approximately 1.3 mM intracellular glutathione, which is insufficient for maximal enzymatic activity. During hyperoxic exposure, this deficit would probably be more significant. Thus the ability of extracellular glutathione along with gamma-glutamyl transpeptidase activity to provide amino acids for de novo glutathione synthesis appears to be a potentially important component of antioxidant defense.
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PMID:Protection of alveolar macrophages from hyperoxia by gamma-glutamyl transpeptidase. 197 90

In addition to its participation in a variety of other biochemical reactions, glutathione (GSH) is a major antioxidant. It is regularly generated intracellularly from its oxidized form by glutathione reductase activity that is coupled with a series of interrelated reactions. Synthesis of GSH also takes place intracellularly by a two-step reaction, the first of which is catalyzed by rate-limiting gamma-glutamylcysteine synthetase activity. Intracellular substrates for GSH are provided both by direct amino acid transport and by a gamma-glutamyl transpeptidase reaction that salvages circulating GSH by coupling the gamma-glutamyl moiety to a suitable amino acid acceptor for transport into the cell. Although the liver is a net synthesizer of circulating GSH, organs such as the kidney salvage GSH through the gamma-glutamyl transpeptidase reaction. Intracellular GSH may be consumed by GSH transferase reactions that conjugate GSH with certain xenobiotics. Elevation of cellular GSH levels in cultured cells in response to hyperoxia or electrophilic agents such as diethylmaleate is coupled with an increase in activity of the Xc- transport system for the amino acids cystine and glutamate. Strategies may be developed for protection against oxidant injury by enhancement of transport systems for precursor amino acids of GSH or by providing substrate that circumvents feedback inhibition of GSH synthesis.
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PMID:Regulation of cellular glutathione. 257 74

Glutathione (GSH) administered intraperitoneally significantly prolongs the time to initial seizure and survival time of rats exposed to hyperbaric hyperoxia (HBO). Acivicin is an antitumor antibiotic that is an inhibitor of gamma-glutamyl transpeptidase (GGT), an enzyme necessary for the breakdown and transport across cell membranes of GSH. To determine whether acivicin treatment alters GSH-induced protection from HBO, rats were dosed with 25 mg/kg of acivicin or vehicle 1 h before O2 exposure at an inspired O2 fraction of 1.0 at 4 ATA. Immediately before exposure, rats received GSH (1 mmol/kg) or vehicle. Time to seizure and time to death were recorded during exposure by direct observation. In separate groups of rats on the same dosing schedule, plasma GSH, renal GGT, and brain GGT were measured 15 min after the GSH injection without HBO exposure and 100 min after the beginning of HBO exposure. Renal GGT was decreased to 2.5% of control and brain GGT to 37% of control in the acivicin-dosed rats. Plasma GSH increased 3-fold in rats given acivicin alone, 52-fold in rats given GSH alone, and 84-fold in rats receiving both acivicin and GSH. Rats dosed with GSH alone had significantly prolonged times to seizure and death compared with all other groups. Rats dosed with GSH after receiving acivicin were not protected from HBO despite the large increase in plasma GSH that occurred in these animals. GSH treatment did not increase tissue GSH in lung, liver, or brain at 160 or 200 min of exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Elimination of glutathione-induced protection from hyperbaric hyperoxia by acivicin. 791 99

By participating in glutathione (GSH) synthesis, gamma-glutamyl transpeptidase (GGT) influences the GSH redox cycle, which is a major contributor in protecting against reactive oxygen metabolites. This study determined the effect of prolonged exposure of neonatal rats to > 98% oxygen on expression of GGT and on GSH metabolism. Lungs of neonatal rats chronically exposed to hyperoxia had increased expression of GGT mRNA, resulting in significantly higher GGT protein levels and enzyme activity than in lungs of animals raised in room air. Hyperoxia also upregulated glucose-6-phosphate dehydrogenase, but Na-K-ATPase activity was not changed. GGT mRNA, protein level, and enzyme activity returned to control levels after recovery in room air for 3 days. Levels of GSH, glutathione disulfide, and protein-bound GSH (S-glutathiolated protein) rose with hyperoxia and fell during recovery. S-glutathiolation is likely a mechanism for protection and a regulatory modification of protein sulfhydryl groups. Hyperoxia-induced upregulation of GGT and the concomitant increase in protein S-glutathiolation appear to be additional components fundamental in protecting the lung against oxidative injury.
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PMID:Hyperoxia enhances expression of gamma-glutamyl transpeptidase and increases protein S-glutathiolation in rat lung. 877 34

We studied the regulation of GSH and the enzymes involved in GSH regulation, gamma-glutamylcysteine synthetase (gamma-GCS) and gamma-glutamyl transpeptidase (gamma-GT), in response to the oxidants menadione, xanthine/xanthine oxidase, hyperoxia, and cigarette smoke condensate in human alveolar epithelial cells (A549). Menadione (100 microM), xanthine/xanthine oxidase (50 microM/10 mU), and cigarette smoke condensate (10%) exposure produced increased GSH levels (240 +/- 6, 202 +/- 12, and 191 +/- 2 nmol/mg protein, respectively; P < 0.001) compared with the control level (132 +/- 8 nmol/mg protein), which were associated with a significant increase in gamma-GCS activity (0.18 +/- 0.006, 0.16 +/- 0.01, and 0.17 +/- 0. 008 U/mg protein, respectively; P < 0.01) compared with the control level (0.08 +/- 0.001 U/mg protein) at 24 h. Exposure to hyperoxia (95% O2) resulted in a time-dependent increase in GSH levels. gamma-GCS activity increased significantly at 4 h (P < 0.001), returning to control values after 12 h of exposure. Dexamethasone (3 microM) exposure produced a significant time-dependent decrease in the levels of GSH and gamma-GCS activity at 24-96 h. The activity of gamma-GT did not change after oxidant treatment; however, it was decreased significantly by dexamethasone at 24-96 h. Thus oxidants and dexamethasone modulate GSH levels and activities of gamma-GT and gamma-GCS by different mechanisms. We suggest that the increase in gamma-GCS activity but not in gamma-GT activity may be required for the increase in intracellular GSH under oxidative stress in alveolar epithelial cells.
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PMID:Differential regulation of glutathione by oxidants and dexamethasone in alveolar epithelial cells. 968 38

Influence of oxygen on lung cell differentiation has been studied in precision-cut rat lung slice cultures. Rat lung slices were positioned on rolling inserts placed into vials with opened caps to allow free access to the gaseous phase. This system was placed into a continuous-flow rotating chamber with controlled pO(2), pCO(2) and hygrometry. Slices were cultured in a serum-free medium up to 3 days under an atmosphere of 21 or 70% oxygen. Cellular antioxidant markers demonstrated an oxygen concentration-dependent response. Slices cultured with 70% oxygen exhibited the highest specific activity of catalase, NADPH cytochrome c reductase and gamma-glutamyl transpeptidase (GGT) as well as the highest levels of intracellular glutathione after 48 or 72 hours of incubation. Moreover, hyperoxic exposure altered the expression of lung manganese-containing superoxide dismutase mRNA. Hyperoxia had little or no effect on intracellular ATP levels, which remained high in lung slices compared with freshly isolated tissue. The study of the pulmonary specific functions allowed to confirm maintenance of the in vitro cellular differentiation of lung slices incubated with 21% oxygen: (i) polyamine transport is preserved and exhibited kinetic properties similar to those observed in lung in vivo; (ii) ATP levels remained constant throughout the time course of incubation. This in vitro model proves to be a useful tool to study mechanisms involved after oxygen exposure and will probably be useful for the study of other environmental gaseous contaminants. Further developments in this method are under development.
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PMID:Characterization of Precision-cut Rat Lung Slices in a Biphasic Gas/Liquid Exposure System: Effect of O(2). 2065 4