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

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%O-2) for 24-72 h or maintained in room air (21%O-2). 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 P-32-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.