Epoxides are three membered cyclic ethers which can be toxic and mutagenic. They are degraded by enzymes known as epoxide hydrolases (EHs), which add water to epoxides to yield more water soluble diols. EHs are widely known for metabolizing xenobiotics, and this project advances our understanding of their fundamental structure, biochemistry and regulation. The soluble epoxide hydrolase (sEH) is the most abundant and active of the EHs in mammals, and it is largely involved in the hydrolysis of endogenous epoxides on natural fatty acids (EpFAs). Since EpFAs are powerful chemical mediators previously shown to reduce inflammation, hypertension, heart failure, and pain, their hydrolysis by the sEH can give rise to disease states. In this project we will test the hypothesis that the levels of EpFA and sEH are influenced by environmental factors, dietary status, and disease states. We also will test if decreasing sEH activity increases EpFA resulting in improved health.
In Aim I, we will investigate the biochemistry of the sEH, as well as the microsomal EH (largely responsible for the metabolism of xenobiotics) and the newly discovered EH3. We will determine the relative roles of the sEH, mEH and EH3 in hydrolysis of bioactive EpFA. These biochemical and structural studies will allow prediction of the biological effects resulting from genetic alterations in human sEH. Anti-microbials in some hand soaps and some drugs are powerful inhibitors of the sEH while other environmental chemicals and drugs are powerful inducers. We will determine how these materials alter biologies regulated by the sEH and EpFA.
Aim II A is expanding analytical methods for regulatory lipids altered by disease states, environmental chemicals and drugs. These methods are being used to address the influence of environmental chemicals and nutrition on the sEH. The biochemical tools from Aim I and the analytical tools from Aim IIA will be used in Aims IIB-D to investigate how changes in the sEH and EpFA alter three separate biologies. In IIB we demonstrate that inhibition of the sEH blocks convulsions and reduces perception of inflammatory and neuropathic pain. With pain, inflammation and hypertension, we have shown that sEH inhibitors are more effective in the presence of epoxides of omega 3 rather than omega 6 fatty acids. With an increase in the use of omega 3 lipids as nutraceuticals and value added ingredients, an appreciation of their health effects is critical. We recently demonstrated EpFA from omega-3 and -6 precursors have opposite effects with sEHI on angiogenesis, allowing sEH inhibitors to reduce tumor growth and metastasis when combined with omega 3 EpFA (Aim IIC). This raises the possibly of new cancer therapeutics but cautions that omega 3 lipids could slow wound healing.
Aim II D addresses how sEH inhibitors block hepatic fibrosis caused by carbon tetrachloride. We will test the hypothesis that there are common mechanisms underlying the largely beneficial biological effects of reduced sEH activity. The results of this project will illustrate the importance of man' total environment, including both xenobiotic exposure and nutrition, on health.
Our investigation of the soluble epoxide hydrolase enzyme and its fatty acid epoxide substrates led to the discovery that environmental chemicals, personal care products, and pharmaceuticals can alter the enzyme's activity and expression, which in turn affects hypertension, inflammation, pain and other biologies. We are now evaluating inhibitors of the enzyme as powerful probes to understand the mechanism by which this unique class of natural regulatory oxidized-lipids works, and we are finding that these inhibitors show promise in reducing pain, the growth of solid tumors and fibrosis. We found that omega 3 fatty acid epoxides interact positively with these enzyme inhibitors, illustrating that man's total environment, including exposure to chemicals as well as dietary nutrients and life-style, has a major role and should be considered in determining effects on human health.
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