Hyperoxia is routinely used to treat respiratory distress and lung inadequacy in preterm and term infants. However, excess oxygen contributes to the development of chronic lung disease (CLD), which is also called bronchopulmonary dysplasia (BPD). The molecular mechanisms of hyperoxia-mediated pulmonary injury are not understood, but reactive oxygen species (ROS), which are also produced by environmental chemicals, are the most likely candidates. The central hypothesis of the proposed research is that pulmonary cytochrome P450 (CYP)1B1 plays a key role in hyperoxic lung injury by (i) acting as a pro-oxidant, leading to enhanced formation of lipid peroxidation products (e.g., F2-isoprostanes, isofurans) that in turn mediate lung injury;(ii) inactivating novel endogenous AHR ligands, which protect against lung injury by inducing CYP1A enzymes;and (iii) exacerbating enhanced formation of ROS-mediated oxidative DNA adducts derived from 8- 5'cyclopurines or lipid peroxidation products, resulting in oxygen-mediated injury. We propose the following Specific Aims. 1. To test the hypothesis mice lacking the gene for Cyp1b1 will be less susceptible to oxygen injury than wild type mice, and that the beneficial effects of Cyp1b1 deletion is augmented by pre-treatment of the mice with the CYP1A/1B inducer, 2-naphthoflavone (BNF) prior to hyperoxic exposures. 2. To test the hypothesis that Cyp1b1-deletion in pulmonary endothelial cells or Clara cells will result in differential susceptibilities to oxygen-mediated lung injury. The specific hypothesis to be tested is that conditional deletion of Cyp1b1 will offer mechanistic information regarding the specific lung cell types that contribute to the protection against hyperoxic lung injury. 3. To test the hypothesis that oxidative DNA adducts contributes mechanistically to lung injury mediated by hyperoxia, and that these adducts will serve as novel biomarkers of hyperoxic lung injury and BPD. The hypothesis to be tested is that lungs of hyperoxic mice deficient in CYP1B1 will display lesser oxidative DNA damage than WT mice, and augmented expression of CYP1A enzymes in the Cyp1b1-null mouse in part contributes to the amelioration of oxidative DNA damage in the Cyp1b1-null mouse. The hypothesis that cyclopurine dinucleotides, i.e. AcA or GcA, or direct adducts resulting from F2-isoprostanes will serve as early biomarkers of BPD will be tested. We will also test the hypothesis that genetic polymorphisms in CYP1B1 are risk factors for the development of BPD in infants. The proposed studies should help in the development of novel strategies for the prevention/treatment of lung diseases (e.g. BPD and ARDS) in humans. Should CYP1B1 play a pro-oxidant roie in hyperoxic lung injury, then CYP1B1 inhibitors could be developed as potential preventive/therapeutic candidates against BPD and other lung diseases mediated by supplemental oxygen (e.g. ARDS) in humans. These studies are also applicable to ROS-mediated disorders caused by environmental chemicals.

Public Health Relevance

Hyperoxia is routinely used in the treatment of respiratory distress and pulmonary insufficiency in preterm and term infants, and in adults with ARDS. However, hyperoxia contributes to the development of chronic lung disease (CLD), also known as bronchopulmonary dysplasia (BPD). This project is aimed at developing novel strategies for the prevention/treatment of lung diseases such as BPD and ARDS in humans.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DKUS-D (02))
Program Officer
Nadadur, Srikanth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code
Veith, Alex C; Bou Aram, Boura'a; Jiang, Weiwu et al. (2018) Mice Lacking the Cytochrome P450 1B1 Gene Are Less Susceptible to Hyperoxic Lung Injury Than Wild Type. Toxicol Sci 165:462-474
Taneja, Guncha; Chu, Chun; Maturu, Paramahamsa et al. (2018) Role of c-Jun-N-Terminal Kinase in Pregnane X Receptor-Mediated Induction of Human Cytochrome P4503A4 In Vitro. Drug Metab Dispos 46:397-404
Veith, Alex; Moorthy, Bhagavatula (2018) ROLE OF CYTOCHROME P450S IN THE GENERATION AND METABOLISM OF REACTIVE OXYGEN SPECIES. Curr Opin Toxicol 7:44-51
Lingappan, Krithika; Maturu, Paramahamsa; Liang, Yanhong Wei et al. (2018) ?-Naphthoflavone treatment attenuates neonatal hyperoxic lung injury in wild type and Cyp1a2-knockout mice. Toxicol Appl Pharmacol 339:133-142
Mallick, Pankajini; Taneja, Guncha; Moorthy, Bhagavatula et al. (2017) Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics-small molecule drug interactions. Expert Opin Drug Metab Toxicol 13:605-616
Lingappan, Krithika; Maity, Suman; Jiang, Weiwu et al. (2017) Role of Cytochrome P450 (CYP)1A in Hyperoxic Lung Injury: Analysis of the Transcriptome and Proteome. Sci Rep 7:642
Shrestha, Amrit Kumar; Patel, Ananddeep; Menon, Renuka T et al. (2017) Leflunomide induces NAD(P)H quinone dehydrogenase 1 enzyme via the aryl hydrocarbon receptor in neonatal mice. Biochem Biophys Res Commun 485:195-200
Mallick, Pankajini; Basu, Sumit; Moorthy, Bhagavtula et al. (2017) Role of Toll-like receptor 4 in drug-drug interaction between paclitaxel and irinotecan in vitro. Toxicol In Vitro 41:75-82
Dinu, Daniela; Chu, Chun; Veith, Alex et al. (2016) Mechanistic role of cytochrome P450 (CYP)1B1 in oxygen-mediated toxicity in pulmonary cells: A novel target for prevention of hyperoxic lung injury. Biochem Biophys Res Commun 476:346-351
Ghose, Romi; Mallick, Pankajini; Taneja, Guncha et al. (2016) In Vitro Approaches to Study Regulation of Hepatic Cytochrome P450 (CYP) 3A Expression by Paclitaxel and Rifampicin. Methods Mol Biol 1395:55-68

Showing the most recent 10 out of 41 publications