Loss of cytochrome P450 (CYP)1B1 mitigates hyperoxia response in adult mouse lung by reprogramming metabolism and translation.

Oxygen supplementation is life saving for premature infants and for COVID-19 patients but can induce long-term pulmonary injury by triggering inflammation, with xenobiotic-metabolizing CYP enzymes playing a critical role. Murine studies showed that CYP1B1 enhances, while CYP1A1 and CYP1A2 protect from, hyperoxic lung injury. In this study we tested the hypothesis that Cyp1b1-null mice would revert hyperoxia-induced transcriptomic changes observed in WT mice at the transcript and pathway level. Wild type (WT) C57BL/6J and Cyp1b1-null mice aged 8-10 weeks were maintained in room air (21% O) or exposed to hyperoxia (>95% O) for 48h. Transcriptomic profiling was conducted using the Illumina microarray platform. Hyperoxia exposure led to robust changes in gene expression and in the same direction in WT, Cyp1a1-, Cyp1a2-, and Cyp1b1-null mice, but to different extents for each mouse genotype. At the transcriptome level, all Cyp1-null murine models reversed hyperoxia effects. Gene Set Enrichment Analysis identified 118 hyperoxia-affected pathways mitigated only in Cyp1b1-null mice, including lipid, glutamate, and amino acid metabolism. Cell cycle genes Cdkn1a and Ccnd1 were induced by hyperoxia in both WT and Cyp1b1-null mice but mitigated in Cyp1b1-null O compared to WT O mice. Hyperoxia gene signatures associated positively with bronchopulmonary dysplasia (BPD), which occurs in premature infants (with supplemental oxygen being one of the risk factors), but only in the Cyp1b1-null mice did the gene profile after hyperoxia exposure show a partial rescue of BPD-associated transcriptome. Our study suggests that CYP1B1 plays a pro-oxidant role in hyperoxia-induced lung injury.