We have recently cloned several new members of the murine CYP2C subfamily, expressed the recombinant P450 proteins in E. coli, and showed that they are active in the metabolism of arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) and/or hydroxyeicosatetraenoic acids (HETEs), eicosanoids that possess potent biological activities in numerous tissues. Despite the fact that these enzymes are 69-92% identical at the amino acid level, they differ markedly in their catalytic turnover and each enzyme has a unique product profile. RT-PCR and immunoblotting studies reveal that CYP2C mRNAs and proteins are abundant in both hepatic and extrahepatic tissues, and that the tissue distribution is P450 isoform-specific. Interestingly, these studies show that the CYP2C proteins are present in high concentrations in the lung. We have recently identified CYP2C29 as the major CYP2C isoform in lung and demonstrated that it is highly expressed in airway epithelial cells. We have cloned the Cyp2c29 gene, characterized its intron-exon organization, and made a targeting construct which will be used to generate Cyp2c29 null mice. These mice will be studied at baseline and after selected stimuli (e.g. allergen exposure, LPS exposure) to determine the role of this P450 in lung function. We have also developed a panel of immunospecific peptide-based antibodies to the murine CYP2C isoforms so that their tissue distribution and regulation can be investigated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES025044-03
Application #
6672856
Study Section
(LPP)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Seubert, John; Yang, Baichun; Bradbury, J Alyce et al. (2004) Enhanced postischemic functional recovery in CYP2J2 transgenic hearts involves mitochondrial ATP-sensitive K+ channels and p42/p44 MAPK pathway. Circ Res 95:506-14
Nelson, David R; Zeldin, Darryl C; Hoffman, Susan M G et al. (2004) Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 14:1-18
DeLozier, Tracy C; Tsao, Cheng-Chung; Coulter, Sherry J et al. (2004) CYP2C44, a new murine CYP2C that metabolizes arachidonic acid to unique stereospecific products. J Pharmacol Exp Ther 310:845-54
Yaghi, Asma; Bend, John R; Webb, Christopher D et al. (2004) Excess nitric oxide decreases cytochrome P-450 2J4 content and P-450-dependent arachidonic acid metabolism in lungs of rats with acute pneumonia. Am J Physiol Lung Cell Mol Physiol 286:L1260-7
Ma, Jixiang; Graves, Joan; Bradbury, J Alyce et al. (2004) Regulation of mouse renal CYP2J5 expression by sex hormones. Mol Pharmacol 65:730-43
Wang, Hong; Zhao, Yun; Bradbury, J Alyce et al. (2004) Cloning, expression, and characterization of three new mouse cytochrome p450 enzymes and partial characterization of their fatty acid oxidation activities. Mol Pharmacol 65:1148-58
Pfister, Sandra L; Spitzbarth, Nancy; Zeldin, Darryl C et al. (2003) Rabbit aorta converts 15-HPETE to trihydroxyeicosatrienoic acids: potential role of cytochrome P450. Arch Biochem Biophys 420:142-52
Wang, Hong; Lin, Li; Jiang, Jiangang et al. (2003) Up-regulation of endothelial nitric-oxide synthase by endothelium-derived hyperpolarizing factor involves mitogen-activated protein kinase and protein kinase C signaling pathways. J Pharmacol Exp Ther 307:753-64
Yaghi, Asma; Bradbury, J Alyce; Zeldin, Darryl C et al. (2003) Pulmonary cytochrome P-450 2J4 is reduced in a rat model of acute Pseudomonas pneumonia. Am J Physiol Lung Cell Mol Physiol 285:L1099-105
Oleksiak, Marjorie F; Wu, Shu; Parker, Carol et al. (2003) Identification and regulation of a new vertebrate cytochrome P450 subfamily, the CYP2Ps, and functional characterization of CYP2P3, a conserved arachidonic acid epoxygenase/19-hydroxylase. Arch Biochem Biophys 411:223-34

Showing the most recent 10 out of 35 publications