Mechanistic Role of Cytochrome P450 1B1 in Hyperoxic Lung Injury
Authors: Veith Alex , Jiang Weiwu , Gastelum Grady , Wang Lihua , Moorthy Bhagavatula 
Published: June 2021

Supplemental oxygen is often used to assist those with respiratory dysfunction, including adults with acute respiratory distress syndrome (ARDS) and bronchopulmonary dysplasia (BPD) in preterm infants. Experimental evidence has shown that increases in oxygen levels can create a hyperoxic environment that is capable of exacerbating existing pulmonary injury as well as independently inducing injury due to increases in reactive oxygen species (ROS) and oxidative stress. Our group has examined the role of cytochrome P450 (CYP) enzymes in hyperoxic toxicity because of their possible role in the generation of ROS. We have previously found that CYP1A1/1A2 as well as the aryl hydrocarbon receptor (AHR), protect against hyperoxic toxicity. We have also found that CYP1B1 may, in fact, contribute to hyperoxic toxicity in vitro and in Cyp1b1‐null mice. Further, we found that Cyp1b1‐null mice exposed to hyperoxia have decreased markers of oxidative stress and increased CYP1A gene expression compared to WT mice. In this study, we hypothesized that Cyp1b1‐null mice would be less susceptible to hyperoxic lung injury compared to WT mice and that CYP1A mechanistically contributes to the attenuated phenotype of Cyp1b1‐null mice. To test this hypothesis, we exposed male and female C57BL/6J (WT), Cyp1b1‐null, Cyp1a1/1b1‐null (DKO), and Cyp1a1/1a2/1b1‐null (TKO) mice to hyperoxia (>95% O2) for 24–68 hours. Lung weight measurements were used to assess pulmonary injury and edema and qPCR was used to measure RNA. We found that all mice lacking CYP1B1, including DKO and TKO mice, had reduced pulmonary injury as indicated by reduced lung weights in male (P<0.01) and female (P<0.05) mice after 68 hours of hyperoxia. CYP1B1 gene expression was induced (P<0.01) in WT mice during hyperoxia exposure, and CYP1A1 gene expression was increased in Cyp1b1‐null mice (P=0.01). NQO1 gene expression was significantly induced by hyperoxia (P<0.05) in all groups with higher expression in TKO mice at room air (P<0.001) and early phase of hyperoxia (P<0.05). We found that pulmonary AHR repressor (AHRR) expression was increased in the DKO and TKO (P<0.05) mice after hyperoxia exposure. Our results suggest that increased AHR‐dependent transcription, as evidenced by enhanced CYP1A1 and AHRR gene expression, may play a role in attenuating lung injury in mice lacking CYP1B1 and needs to be elucidated further. Future studies will thoroughly characterize the effect of CYP1B1 on oxidative stress in these animals and determine the viability of CYP1B1‐directed therapeutics to treat or prevent ARDS/BPD.Support or Funding InformationResearch reported in this publication was supported by the National Institutes of Health under award number R01ES019689, R01ES009132, R01HL12516, R01HL129794, and R01HL087174 to B.M. and T32GM088129 to A.V. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.