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)

The effect of hyperoxia (O2 > 95%) for 48 hours on the induction of pulmonary and hepatic cytochrome P450 has been investigated in adult male rats. Northern blot analysis using six "specific" oligonucleotide probes indicated that CYP 1A1 and CYP 1A2 mRNAs in liver and CYP 1A1 mRNA in lung were significantly increased by hyperoxic exposure, whereas the major constitutive P450 mRNAs, CYP 2C11 in liver and CYP 2B1 in lung, were decreased. Since induction of CYP 1A1 has only been reported with the use of exogenously administered xenobiotics, further studies were carried out to confirm the results obtained with Northern blot analysis. cDNAs were synthesized for CYP 1A1 and 1A2 in the liver and CYP 1A1 in the lungs and amplified by reverse PCR. These results indicate that these cDNAs were amplified significantly more in the hyperoxia group than in the control animals. Futhermore, CYP 1A1 and 1A2 proteins in liver and CYP 1A1 protein in lungs as well as the corresponding monooxygenase activities were increased by hyperoxia. Hyperoxic induction of CYP 1A1 and 1A2 is the first demonstration of nonexogenous CYP 1A induction in animals and indicates the needs to pursue the changes of Ah receptor-ligand-DNA interaction in hyperoxia.
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PMID:Induction of cytochrome P450 1A1 and 1A2 by hyperoxia. 826 28

Administration of supplemental oxygen is frequently encountered in infants suffering from pulmonary insufficiency and in adults with acute respiratory distress syndrome. However, hyperoxia causes acute lung damage in experimental animals. In the present study, we investigated the roles of the Ah receptor (AHR) in the modulation of cytochrome P4501A (CYP1A) enzymes and in the development of lung injury by hyperoxia. Adult male wild-type [AHR (+/+)] mice and AHR-deficient animals [AHR (-/-)] were maintained in room air or exposed to hyperoxia (>95% oxygen) for 24 to 72 h, and pulmonary and hepatic expression of CYP1A and lung injury were studied. Hyperoxia caused significant increases in pulmonary and hepatic CYP1A1 activities (ethoxyresorufin O-deethylase) and mRNA levels in wild-type (C57BL/6J) AHR (+/+), but not AHR (-/-) mice, suggesting that AHR-dependent mechanisms contributed to CYP1A1 induction. On the other hand, hyperoxia augmented hepatic CYP1A2 expression in both wild-type and AHR (-/-) animals, suggesting that AHR-independent mechanisms contributed to the CYP1A2 regulation by hyperoxia. AHR (-/-) mice exposed to hyperoxia were more susceptible than wild-type mice to lung injury and inflammation, as indicated by significantly higher lung weight/body weight ratios, increased pulmonary edema, and enhanced neutrophil recruitment into the lungs. In conclusion, our results support the hypothesis that the hyperoxia induces CYP1A1, but not CYP1A2, expression in vivo by AHR-dependent mechanisms, a phenomenon that may mechanistically contribute to the beneficial effects of the AHR in hyperoxic lung injury.
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PMID:Disruption of the Ah receptor gene alters the susceptibility of mice to oxygen-mediated regulation of pulmonary and hepatic cytochromes P4501A expression and exacerbates hyperoxic lung injury. 1512 65

Supplemental oxygen, used to treat pulmonary insufficiency in newborns, contributes to the development of bronchopulmonary dysplasia (BPD). Cytochrome P4501A enzymes are induced by hyperoxia in animal models, but their role in human systems is unknown. Here we investigated the molecular mechanisms of induction of CYP1A1 by hyperoxia in human lung cell lines. Three human lung cell lines were exposed to hyperoxia (95% O2) for 0-72 h, and CYP1A1 activities, apoprotein contents, and mRNA levels were determined. Hyperoxia significantly induced CYP1A1 activity and protein contents (2-4 fold), and mRNA levels (30-40 fold) over control in each cell line. Transfection of a CYP1A1 promoter/luciferase reporter construct, followed by hyperoxia (4-72 h), showed marked (2-6 fold) induction of luciferase expression. EMSA and siRNA experiments strongly suggest that the Ah receptor (AHR) is involved in the hyperoxic induction of CYP1A1. MTT reduction assays showed attenuation of cell injury with the CYP1A1 inducer beta-naphthoflavone (BNF). Our results strongly suggest that hyperoxia transcriptionally activates CYP1A1 expression in human lung cell lines by AHR-dependent mechanisms, and that CYP1A1 induction is associated with decreased toxicity. This novel finding of induction of CYP1A1 in the absence of exogenous AHR ligands could lead to novel interventions in the treatment of BPD.
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PMID:Regulation of cytochrome P4501A1 expression by hyperoxia in human lung cell lines: Implications for hyperoxic lung injury. 1882 9

Hyperoxia-induced oxidative stress contributes to the pathogenesis of bronchopulmonary dysplasia (BPD), the most common respiratory morbidity of preterm infants. Importantly, the disease lack specific therapies and is associated with long-term cardio-pulmonary and neurodevelopmental morbidities, signifying the need to discover novel therapies and decrease the disease burden. We and others have demonstrated that leflunomide, a food and drug administration approved drug to treat humans with rheumatoid arthritis, increases the expression of the anti-oxidant enzymes, NAD(P)H quinone dehydrogenase 1 (NQO1), catalase, and superoxide dismutase (SOD). However, whether this drug can decrease oxidative stress in fetal human pulmonary arterial endothelial cells (HPAECs) is unknown. Therefore, we tested the hypothesis that leflunomide will decrease hyperoxia-induced oxidative stress by upregulating these anti-oxidant enzymes in HPAECs. Leflunomide decreased hydrogen peroxide (H2O2) levels and increased the mRNA and protein levels of catalase, NQO1, and SOD2 in HPAECs at basal conditions. Further, leflunomide-treated cells continued to have decreased H2O2 and increased SOD2 levels upon hyperoxia exposure. Leflunomide did not affect the expression of other anti-oxidant enzymes, including hemoxygenase-1 and SOD1. AhR-knockdown experiments suggested that leflunomide regulated NQO1 levels via AhR-dependent mechanisms and H2O2, catalase, and SOD2 levels via AhR-independent mechanisms. Collectively, the results support the hypothesis that leflunomide decreases oxidative stress in HPAECs via SOD2-and catalase-dependent, but AhR- and NQO1-independent mechanisms. Our findings indicate that leflunomide is a potential drug for the management of BPD in preterm infants.
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PMID:Leflunomide attenuates oxidative stress in fetal human lung endothelial cells via superoxide dismutase 2 and catalase. 3007 71