The long-term objective of this research project is to determine the toxicological and clinical significance of a unique class of cytotoxic compounds, namely, the diol metabolites of monoepoxides of linoleic acid (leukotoxin and isoleukotoxin). These monoepoxides are found at high levels in the serum of patients with severe burns and acute respiratory distress syndrome (ARDS) and was shown to cause coronary cardiac arrest and severe lung edema in experimental animals. Recent results by the investigator, however, show that leukotoxin and isoleukotoxin are toxic only in cells which contain epoxide hydrolase. This suggests that the pathological effects previously attributed to the epoxides are actually due to the diol metabolites. Based on these results, the specific aims of this application are to: (1) Chemically synthesize the monoepoxides and corresponding diol isomers of linoleic acid, (2) Analyze the biological activity of these synthesized compounds using in vitro (cardiac myocytes) and transgenic mouse models, (3) Use a heterologous expression system to identify human enzyme pathways which lead to the production of these compounds, and (4) Identify and quantify these compounds in the serum of patients with acute respiratory distress syndrome.
These specific aims are designed to test the hypothesis that linoleic acid diols directly cause or mediate effects that were previously attributed to the parent epoxides and that enzymatically catalyzed diol formation is the rate limiting step. This work will provide a basis for developing specific inhibitors of epoxide hydrolases in order to prevent the formation of these compounds during acute inflammation in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM056708-04
Application #
6500945
Study Section
Special Emphasis Panel (ZRG4-ALTX-1 (01))
Program Officer
Okita, Richard T
Project Start
1998-03-01
Project End
2003-05-31
Budget Start
2001-08-01
Budget End
2003-05-31
Support Year
4
Fiscal Year
2000
Total Cost
$85,800
Indirect Cost
Name
University of Connecticut
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269
Koerner, Ines P; Jacks, Rachel; DeBarber, Andrea E et al. (2007) Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to neuronal survival after ischemic injury. J Neurosci 27:4642-9
Yang, Jie; Morton, Martha D; Hill, Dennis W et al. (2006) NMR and HPLC-MS/MS analysis of synthetically prepared linoleic acid diol glucuronides. Chem Phys Lipids 140:75-87
Enayetallah, Ahmed E; French, Richard A; Grant, David F (2006) Distribution of soluble epoxide hydrolase, cytochrome P450 2C8, 2C9 and 2J2 in human malignant neoplasms. J Mol Histol 37:133-41
Enayetallah, Ahmed E; French, Richard A; Barber, Michele et al. (2006) Cell-specific subcellular localization of soluble epoxide hydrolase in human tissues. J Histochem Cytochem 54:329-35
Enayetallah, Ahmed E; Grant, David F (2006) Effects of human soluble epoxide hydrolase polymorphisms on isoprenoid phosphate hydrolysis. Biochem Biophys Res Commun 341:254-60
Nowak, Grazyna; Grant, David F; Moran, Jeffery H (2004) Linoleic acid epoxide promotes the maintenance of mitochondrial function and active Na+ transport following hypoxia. Toxicol Lett 147:161-75
Enayetallah, Ahmed E; French, Richard A; Thibodeau, Michael S et al. (2004) Distribution of soluble epoxide hydrolase and of cytochrome P450 2C8, 2C9, and 2J2 in human tissues. J Histochem Cytochem 52:447-54
Srivastava, Punit K; Sharma, Vikas K; Kalonia, Davendra S et al. (2004) Polymorphisms in human soluble epoxide hydrolase: effects on enzyme activity, enzyme stability, and quaternary structure. Arch Biochem Biophys 427:164-9
Przybyla-Zawislak, Beata D; Srivastava, Punit K; Vazquez-Matias, Johana et al. (2003) Polymorphisms in human soluble epoxide hydrolase. Mol Pharmacol 64:482-90
Lecka-Czernik, Beata; Moerman, Elena J; Grant, David F et al. (2002) Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 143:2376-84

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