Mice Lacking the Cytochrome P450 1B1 Gene Are Less Susceptible to Hyperoxic Lung Injury Than Wild Type.

Abstract

Supplemental oxygen is a life-saving intervention administered to individuals suffering from respiratory distress, including adults with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Despite the clinical benefit, supplemental oxygen can create a hyperoxic environment that increases reactive oxygen species, oxidative stress, and lung injury. We have previously shown that cytochrome P450 (CYP)1A enzymes decrease susceptibility to hyperoxia-induced lung injury. In this investigation, we determined the role of CYP1B1 in hyperoxic lung injury in vivo. Eight- to ten-week old C57BL/6 wild type (WT) and Cyp1b1-/- mice were exposed to hyperoxia (>95% O2) for 24-72 h or maintained in room air (21% O2). Lung injury was assessed by histology and lung weight to body weight (LW/BW) ratios. Extent of inflammation was determined by assessing pulmonary neutrophil infiltration and cytokine levels. Lipid peroxidation markers were quantified by gas chromatography mass spectrometry, and oxidative DNA adducts were quantified by 32P-postlabeling as markers of oxidative stress. We found that Cyp1b1-/- mice displayed attenuation of lung weight and pulmonary edema, particularly after 48-72 h of hyperoxia compared with WT controls. Further, Cyp1b1-/- mice displayed decreased levels of pulmonary oxidative DNA adducts and pulmonary isofurans after 24 h of hyperoxia. Cyp1b1-/- mice also showed increased pulmonary CYP1A1 and 1A2 and mRNA expression. In summary, our results support the hypothesis that Cyp1b1-/- mice display decreased hyperoxic lung injury than wild type counterparts and that CYP1B1 may act as a pro-oxidant during hyperoxia exposure, contributing to increases in oxidative DNA damage and accumulation of lipid hydroperoxides.

• Authors: Alex C Veith, Boura'a Bou Aram, Weiwu Jiang, Lihua Wang, Guodong Zhou, Colin R Jefcoate, Xanthi I Couroucli, Krithika Lingappan, Bhagavatula Moorthy
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 165 Issue 2 Pg. 462-474 (10 01 2018) ISSN: 1096-0929 [Electronic] United States
• PMID: 29939353 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lipid Peroxides
• Cyp1b1 protein, mouse
• Cytochrome P-450 CYP1B1

Topics

• Acute Lung Injury (enzymology, etiology, pathology)
• Animals
• Cytochrome P-450 CYP1B1 (genetics)
• DNA Damage
• Disease Models, Animal
• Hyperoxia (complications, enzymology, pathology)
• Lipid Peroxidation (genetics)
• Lipid Peroxides (metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Oxidative Stress (genetics)