Induction and decline of hepatic cytochromes P4501A1 and 1A2 in rats exposed to hyperoxia are not paralleled by changes in glutathione S-transferase-α

doi:10.1016/S0378-4274(96)03832-5

Toxicology Letters

Volume 90, Issue 1, 15 January 1997, Pages 67-75

https://doi.org/10.1016/S0378-4274(96)03832-5 Get rights and content

Abstract

We investigated the effects of hyperoxia on the activities of hepatic ethoxyresorufin 0-deethylase (EROD) (CYP1A1), methoxyresorufin 0-demethylase (MROD) (CYP1A2), and glutathione transferase-α (GST-α), and the status of protein thiols (PSH) in male Sprague-Dawley rats. Twenty-four h of hyperoxia more than doubled EROD and MROD activities, which were increased 7.6- and 3.3-fold, respectively, after 48 h of hyperoxia. The increases in EROD and MROD activities were paralleled by enhanced CYP1A1/1A2 apoproteins contents, as detected by Western analysis. At 60 h of hyperoxia, by which time hyperoxic Sprague-Dawley rats display marked respiratory distress, pulmonary edema, and other markers of pulmonary dysfunction, the activities and levels of hepatic CYP1A1 and 1A2 had declined dramatically and returned to levels observed in air-breathing control animals. Hepatic activities of GST-α, as well as PSH status, were not altered significantly in the hyperoxic animals at any time point. The marked induction and subsequent decline of hepatic CYP1A1/1A2 activities in rats exposed to hyperoxia suggest that these enzymes may contribute to the mechanisms of injury and/or to adaptive responses to hyperoxic exposures in vivo.

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Exposure to supraphysiological concentrations of oxygen (hyperoxia) leads to bronchopulmonary dysplasia (BPD), one of the most common pulmonary morbidities in preterm neonates, which is more prevalent in males than females. Beta-naphthoflavone (BNF) is protective against hyperoxic lung injury in adult and neonatal wild type (WT) mice and in and mice lacking Cyp1a1gene. In this investigation, we tested the hypothesis that BNF treatment will attenuate neonatal hyperoxic lung injury in WT and Cyp1a2 −/− mice, and elucidated the effect of sex-specific differences. Newborn WT or Cyp1a2 −/− mice were treated with BNF (10 mg/kg) or the vehicle corn oil (CO) i.p., from postnatal day (PND) 2 to 8 once every other day, while being maintained in room air or hyperoxia (85% O2) for 14 days. Hyperoxia exposure lead to alveolar simplification and arrest in angiogenesis in WT as well as Cyp1a2 −/− mice No significant differences were seen between WT and Cyp1a2 −/− mice. Cyp1a2 −/− female mice had better preservation of pulmonary angiogenesis at PND15 compared to similarly exposed males. BNF treatment attenuated lung injury and inflammation in both genotypes, and this was accompanied by a significant induction of hepatic and pulmonary CYP1A1 in WT but not in Cyp1a2 −/− mice. BNF treatment increased NADPH quinone oxidoreductase (NQO1) mRNA levels in Cyp1a2 −/− mouse livers compared to WT mice. These results suggest that BNF is protective in neonatal mice exposed to hyperoxia independent of CYP1A2 and this may entail the protective effect of phase II enzymes like NQO1.
Hyperoxia-mediated transcriptional activation of cytochrome P4501A1 (CYP1A1) and decreased susceptibility to oxygen-mediated lung injury in newborn mice
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Citation Excerpt :
The CYP1A family comprises of two proteins, i.e. CYP1A1 and 1A2, which are induced by polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene or 3-methylcholanthrene [15]. Earlier work in rat and mouse models has shown that hyperoxia induces CYP1A enzymes [9,12,13,16–18], but the underlying mechanisms are not fully understood. We showed earlier that in adult mice, hyperoxia-mediated induction of CYP1A enzymes involves the arylhydrocarbon receptor (AHR) [18], which is the transcription factor that plays a pivotal role in the regulation of CYP1A genes [19–23].
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Research articleInduction and decline of hepatic cytochromes P4501A1 and 1A2 in rats exposed to hyperoxia are not paralleled by changes in glutathione S-transferase-α

Abstract

Clin. Chest Med.

Pharmacol. Ther.

Biochem. Biophys. Res. Commun.

Free Rad. Biol. Med.

Biochem. Pharmacol.

Anal. Biochem.

J. Biol. Chem.

Anal. Biochem.

Toxicology

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

Biochem. Biophys. Acta.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

Biochem. Biophys. Res. Commun.

Pulmonary oxygen toxieity: a review

Pharmacol. Rev.

Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria

J. Biol. Chem.

The molecular biology of cytochrome P450s

Pharmacol. Rev.

Enzymatic oxidation of xenobiotic chemicals

CRC Crit. Rev. Biochem. Mol. Biol.

Multiplicity of mammalian cytoehrome P450

Pharmacol. Rev.

Purification and characterization of liver microsomal cytoehrome P450: electrophoretic, spectral, catalytic, and immunochemical properties and inducibility of eight isozymes isolated from rats treated with phenobarbital or β -naphthoflavone

Biochemistry

The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature

DNA Cell Biol.

Research article
Induction and decline of hepatic cytochromes P4501A1 and 1A2 in rats exposed to hyperoxia are not paralleled by changes in glutathione S-transferase-α