Rat Cytosolic Epoxide Hydrolase

Oesch, Franz; Schladt, Ludwig; Hartmann, Renate; Timms, Christopher; Wörner, Walter

doi:10.1007/978-1-4684-5134-4_16

Cited by 17 publications

(17 citation statements)

References 17 publications

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“…7c), an eVect mediated by the transcription factor peroxisome proliferator activated receptor (PPAR) (Oesch et al 1986;Lundgren et al 1987;Johansson et al 1995), which suggests a possible role of sEH in PP induced liver cancerogenesis. A PPAR mediated induction of sEH in humans has not yet been detected.…”

Section: Cellular Distributionmentioning

confidence: 99%

Mammalian epoxide hydrolases in xenobiotic metabolism and signalling

2009

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Epoxide hydrolases catalyse the hydrolysis of electrophilic-and therefore potentially genotoxic-epoxides to the corresponding less reactive vicinal diols, which explains the classiWcation of epoxide hydrolases as typical detoxifying enzymes. The best example is mammalian microsomal epoxide hydrolase (mEH)-an enzyme prone to detoxiWcation-due to a high expression level in the liver, a broad substrate selectivity, as well as inducibility by foreign compounds. The mEH is capable of inactivating a large number of structurally diVerent, highly reactive epoxides and hence is an important part of the enzymatic defence of our organism against adverse eVects of foreign compounds. Furthermore, evidence is accumulating that mammalian epoxide hydrolases play physiological roles other than detoxiWcation, particularly through involvement in signalling processes. This certainly holds true for soluble epoxide hydrolase (sEH) whose main function seems to be the turnover of lipid derived epoxides, which are signalling lipids with diverse functions in regulatory processes, such as control of blood pressure, inXammatory processes, cell proliferation and nociception. In recent years, the sEH has attracted attention as a promising target for pharmacological inhibition to treat hypertension and possibly other diseases. Recently, new hitherto uncharacterised epoxide hydrolases could be identiWed in mammals by genome analysis. The expression pattern and substrate selectivity of these new epoxide hydrolases suggests their participation in signalling processes rather than a role in detoxiWcation. Taken together, epoxide hydrolases (1) play a central role in the detoxiWcation of genotoxic epoxides and (2) have an important function in the regulation of physiological processes by the control of signalling molecules with an epoxide structure.

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Section: Cellular Distributionmentioning

confidence: 99%

Mammalian epoxide hydrolases in xenobiotic metabolism and signalling

2009

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“…The prototypic substrate used to distinguish sEH activity from microsomal epoxide hydrolase activity is trans-stilbene oxide (Fig. 1) [51]. Other more sensitive radiometric substrates have been developed for sEH [53].…”

Section: Substrates and Inhibitorsmentioning

confidence: 99%

“…Further studies have indicated the presence of genetic polymorphism at the sEH gene locus [46]. Rodent species exhibit an induction of sEH activity when treated with peroxisomal proliferator agents, such as 2,4-dichlorophenoyacetic acid and Wyeth 14.643, and hypolipidemic drugs, such as clofibrate [47][48][49][50][51]. The mechanism of this induction has not been investigated, but involves likely the peroxisomal proliferator-activated receptor a pathway.…”

Section: Introductionmentioning

confidence: 99%

Epoxide hydrolases: biochemistry and molecular biology

Fretland

Omiecinski

2000

Chemico-Biological Interactions

273

185

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Epoxides are organic three-membered oxygen compounds that arise from oxidative metabolism of endogenous, as well as xenobiotic compounds via chemical and enzymatic oxidation processes, including the cytochrome P450 monooxygenase system. The resultant epoxides are typically unstable in aqueous environments and chemically reactive. Biol. Chem. 260 (1985) 1630-1640). Therefore, it is of vital importance for the biological organism to regulate levels of these reactive species. The epoxide hydrolases (E.C. 3.3.2.3) belong to a sub-category of a broad group of hydrolytic enzymes that include esterases, proteases, dehalogenases, and lipases Beetham et al. (DNA Cell Biol. 14 (1995) 61 -71). In particular, the epoxide hydrolases are a class of proteins that catalyze the hydration of chemically reactive epoxides to their corresponding dihydrodiol products. Simple epoxides are hydrated to their corresponding vicinal dihydrodiols, and arene oxides to trans-dihydrodiols. In general, this hydration leads to more stable and less reactive intermediates, however exceptions do exist. In mammalian species, there are at least five epoxide hydrolase forms, microsomal cholesterol 5,6-oxide hydrolase, hepoxilin A 3 hydrolase, leukotriene A 4 hydrolase, soluble, and microsomal epoxide hydrolase. Each of these enzymes is distinct chemically and immunologically. Table 1 illustrates some general properties for each of these classes of hydrolases. Fig. 1 provides an overview of selected model substrates for each class of epoxide hydrolase.

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“…However, there may be other endogenous substrates, and the biological role of the phosphatase activity is unknown [19]. sEH activity is highest in mammalian liver and kidney [20][21][22][23], but it has also been found in many other tissues. In humans and rodents sEH expression occurs in liver, kidney, lung, heart, gut, brain, placenta, bladder, prostate, testis, spleen, skin, ovary, vascular endothelium, and some smooth muscle [13,17,[24][25][26][27][28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have shown that sEH can be regulated by endogenous chemical mediators and by some xenobiotics. 1) The sEH is induced by the administration of agonists of peroxisome proliferator activated receptor alpha (PPAR-alpha) in rodents [23,31,33]. Most organisms appear to respond to these agonists with a 2-to 3-fold increase in hepatic sEH activity.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of the human soluble epoxide hydrolase gene EPHX2

Tanaka

Kamita

Wolf

et al. 2008

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Soluble epoxide hydrolase (sEH) is a multifunctional protein encoded by the EPHX2 gene. The biological functions and enzyme kinetics of sEH have been extensively investigated, however, little is known about its transcriptional regulation and mechanisms of tissue specific expression. Here, a luciferase gene based reporter assay was used to identify the minimal promoter and cis regulatory elements of EPHX2. The minimal promoter was identified as a GC-rich region between nts −374 to +28 with respect to the putative transcriptional start site. A reporter plasmid carrying this minimal promoter showed higher or similar activities in comparison to a reporter plasmid carrying nts −5,974 to +28 of EPHX2 in 9 human cell lines that were tested. Sp1 binding sites that are involved in augmenting the minimal promoter activity of EPHX2 were identified by nested deletion analysis, site-specific mutation, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay.

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Rat Cytosolic Epoxide Hydrolase

Cited by 17 publications

References 17 publications

Mammalian epoxide hydrolases in xenobiotic metabolism and signalling

Mammalian epoxide hydrolases in xenobiotic metabolism and signalling

Epoxide hydrolases: biochemistry and molecular biology

Transcriptional regulation of the human soluble epoxide hydrolase gene EPHX2

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