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)

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

When bovine pulmonary artery endothelial monolayers were exposed to hyperoxia (95% O2 and 5% Co2), they responded by selectively elevating the intracellular concentration of glutathione without affecting the activities of glutathione peroxidase or glutathione reductase, L-2-Oxothiazolidine-4-carboxylate, an intracellular cysteine-delivering agent, further enhanced the intracellular concentration of glutathione in oxygen-exposed endothelial cells and protected them from the lethal effect of hyperoxia. In contrast, buthionine sulfoximine, a potent inhibitor of gamma-glutamylcysteine synthetase, reduced the glutathione concentration and rendered the cells more sensitive to the toxic effect of oxygen. Both L-2-oxothiazolidine-4-carboxylate and buthionine sulfoximine had no effect on the activities of glutathione peroxidase or glutathione reductase. Our results suggest that L-2-oxothiazolidine-4-carboxylate may have the potential of preventing oxygen toxicity.
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PMID:L-2-oxothiazolidine-4-carboxylate protects cultured endothelial cells against hyperoxia-induced injury. 327 Mar 44

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

Induction or overexpression of pulmonary manganese superoxide dismutase (MnSOD) has been shown to protect against oxygen (O2) toxicity. Genetic inactivation of MnSOD (Sod2) results in multiple organ failure and early neonatal death. However, lungs or O2-tolerance of Sod2 knockout mice have not been investigated. We evaluated survival, lung histopathology, and other pulmonary antioxidants (glutathione cycle) of homozygous (-/-) and heterozygous (+/-) Sod2 mutant mice compared with wild-type controls (Sod2+/+) following 48 h exposure to either room air or to O2. The ability of antioxidant N-acetylcysteine to compensate for the loss of MnSOD was explored. Mortality of Sod2-/- mice increased from 0% in room air to 18 and 83% in 50 and 80% O2, respectively. N-acetylcysteine did not alter mortality of Sod2-/- mice. Histopathological analysis revealed abnormalities in saccules of Sod2-/- mice exposed either to room air or to 50% O2 suggestive of delayed postnatal lung development. In 50% O2, activities of glutamate-cysteine ligase (GCL) (previously known as gamma-glutamylcysteine synthetase, gamma-GCS) and glutathione peroxidase increased in Sod2-/- (35 and 70%, respectively) and Sod2+/- (12 and 70%, respectively) mice, but glutathione levels remained unaltered. We conclude that MnSOD is required for normal O2 tolerance and that in the absence of MnSOD there is a compensatory increase in pulmonary glutathione-dependent antioxidant defense in hyperoxia.
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PMID:Increased sensitivity of homozygous Sod2 mutant mice to oxygen toxicity. 1179 7