To safeguard human and environmental health in a cost effective manner, we must develop a mechanistic basis for predicting toxic risk and assessing environmental exposure. We will address aspects of these goals by developing an understanding of the biochemistry, regulation, and toxicological significance of hydrolytic pathways of metabolism. We have targeted two groups of enzymes both of which are induced by peroxisome proliferators and which add water to xenobiotics. Since the epoxide functionality is the reactive center of some of the most dangerous mutagens, carcinogens and toxins known, the cytosolic epoxide hydrolase (cEH) is targeted in objective I. Based on our recent isolation of the message and gene of the cEH, we will examine its regulation and subcellular targeting. Parallel approaches in photoaffinity labeling, amino acid modification, enzyme kinetics and site directed mutagenicity are being used to determine catalytic mechanism. This information will be used to design more effective substrates and inhibitors. All of the above technology will be used to test the hypothesis that the cEH has an endogenous role in the biosynthesis of diols and tetrahydrofuran diols of a variety of lipids including arachidonic acid. Similar approaches will be used to assess the in vitro and in vivo roles of cEH in ameliorating toxicity. Our second objective emphasizes the carboxylesterases which metabolize esters such as malathion, permethrin and a variety of pharmaceuticals. Similar techniques will be used. We will purify hepatic esterases using esterase specific affinity columns that we have designed based upon potent transition state mimics of the enzymes. Based on this work we will isolate cDNA and genomic clones as in objective I and use these to study the regulation of the enzymes. We are investigating the catalytic mechanism of esterases relying heavily on production of mutants in the baculovirus expression system. We are using a new class of spectral substrates yielding highly sensitive assays to monitor serum and tissue esterases following xenobiotic exposure. The above information will be used to extend our appreciation of the role of esterases in the metabolism on natural and man made toxins.
| Kodani, Sean D; Wan, Debin; Wagner, Karen M et al. (2018) Design and Potency of Dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors. ACS Omega 3:14076-14086 |
| Ren, Qian; Ma, Min; Yang, Jun et al. (2018) Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson's disease. Proc Natl Acad Sci U S A 115:E5815-E5823 |
| Pecic, Stevan; Zeki, Amir A; Xu, Xiaoming et al. (2018) Novel piperidine-derived amide sEH inhibitors as mediators of lipid metabolism with improved stability. Prostaglandins Other Lipid Mediat 136:90-95 |
| Yamanashi, Haruto; Boeglin, William E; Morisseau, Christophe et al. (2018) Catalytic activities of mammalian epoxide hydrolases with cis and trans fatty acid epoxides relevant to skin barrier function. J Lipid Res 59:684-695 |
| Wang, Fuli; Zhang, Hongyong; Ma, Ai-Hong et al. (2018) COX-2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor Efficacy of Cisplatin. Mol Cancer Ther 17:474-483 |
| Napimoga, M H; Rocha, E P; Trindade-da-Silva, C A et al. (2018) Soluble epoxide hydrolase inhibitor promotes immunomodulation to inhibit bone resorption. J Periodontal Res 53:743-749 |
| Blöcher, René; Wagner, Karen M; Gopireddy, Raghavender R et al. (2018) Orally Available Soluble Epoxide Hydrolase/Phosphodiesterase 4 Dual Inhibitor Treats Inflammatory Pain. J Med Chem 61:3541-3550 |
| Hao, Lei; Kearns, Jamie; Scott, Sheyenne et al. (2018) Indomethacin Enhances Brown Fat Activity. J Pharmacol Exp Ther 365:467-475 |
| Yang, Yang-Ming; Sun, Dong; Kandhi, Sharath et al. (2018) Estrogen-dependent epigenetic regulation of soluble epoxide hydrolase via DNA methylation. Proc Natl Acad Sci U S A 115:613-618 |
| Stevens, Jacqueline S; Gray, Mary C; Morisseau, Christophe et al. (2018) Endocervical and Neutrophil Lipoxygenases Coordinate Neutrophil Transepithelial Migration to Neisseria gonorrhoeae. J Infect Dis 218:1663-1674 |
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