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      Newborn Mice Lacking the Gene for Cyp1a1 Are More Susceptible to Oxygen-Mediated Lung Injury, and Are Rescued by Postnatal β-Naphthoflavone Administration: Implications for Bronchopulmonary Dysplasia in Premature Infants

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          Abstract

          Prolonged hyperoxia contributes to bronchopulmonary dysplasia (BPD) in preterm infants. β-Naphthoflavone (BNF) is a potent inducer of cytochrome P450 (CYP)1A enzymes, which have been implicated in hyperoxic injuries in adult mice. In this investigation, we tested the hypothesis that newborn mice lacking the Cyp1a1 gene would be more susceptible to hyperoxic lung injury than wild-type (WT) mice and that postnatal BNF treatment would rescue this phenotype by mechanisms involving CYP1A and/or NAD(P)H quinone oxidoreductase (NQO1) enzymes. Newborn WT or Cyp1a1-null mice were treated with BNF (10 mg/kg) or the vehicle corn oil (CO) i.p., from postnatal day (PND) 2 to 14 once every other day, while being maintained in room air or hyperoxia (85% O 2) for 14 days. Both genotypes showed lung injury, inflammation, and alveolar simplification in hyperoxia, with Cyp1a1-null mice displaying increased susceptibility compared to WT mice. BNF treatment resulted in significant attenuation of lung injury and inflammation, with improved alveolarization in both WT and Cyp1a1-null mice. BNF exposed normoxic or hyperoxic WT mice showed increased expression of hepatic CYP1A1/1A2, pulmonary CYP1A1, and NQO1 expression at both mRNA and protein levels, compared with vehicle controls. However, BNF caused greater induction of hepatic CYP1A2 and pulmonary NQO1 enzymes in the Cyp1a1-null mice, suggesting that BNF protects against hyperoxic lung injury in WT and Cyp1a1-null mice through the induction of CYP1A and NQO1 enzymes. Further studies on the protective role of flavonoids against hyperoxic lung injury in newborns could lead to novel strategies for the prevention and/or treatment of BPD.

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          Author and article information

          Journal
          Toxicol Sci
          Toxicol. Sci
          toxsci
          Toxicological Sciences
          Oxford University Press
          1096-6080
          1096-0929
          May 2017
          13 February 2017
          01 May 2018
          : 157
          : 1
          : 260-271
          Affiliations
          [* ]Section of Neonatology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas 77030;
          []Department of Pathology and Genomic Medicine, The Methodist Hospital Physician Organization, Houston, Texas 77030
          Author notes
          [1 ]To whom correspondence should be addressed at Section of Neonatology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC 530.01, Houston, TX 77030. Fax: (832) 8253204. E-mail: xanthic@ 123456bcm.edu
          Article
          PMC5837454 PMC5837454 5837454 kfx036
          10.1093/toxsci/kfx036
          5837454
          28201809
          82487bad-3f92-44bc-86c4-3984c8b7f612
          © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
          History
          Page count
          Pages: 12
          Funding
          Funded by: National Institutes of Health 10.13039/100000002
          Award ID: R01HL088343 to X.C., K08-HL-127103 to K.L. and R01 grants ES-019689, ES-001932, HL-129794, and HL-112516 to B.M.
          Categories
          Cyp1a1 and Oxygen-Mediated Lung Injury

          lung,oxidative injury,β-naphthoflavone,cytochrome P4501A1,newborn,bronchopulmonary dysplasia.

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