Publications

• Epoxide hydrolases: biochemistry and molecular biology.

  Fretland A.J., Omiecinski C.J.

  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 envi ... >> More

  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. In the case of xenobiotics and certain endogenous substances, epoxide intermediates have been implicated as ultimate mutagenic and carcinogenic initiators Adams et al. (Chem. Biol. Interact. 95 (1995) 57-77) Guengrich (Properties and Metabolic roles 4 (1982) 5-30) Sayer et al. (J. 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. << Less

  Chem Biol Interact 129:41-59(2000) [PubMed] [EuropePMC]

  This publication is cited by 4 other entries.

• Formation and metabolism of hepoxilin A3 by the rat brain.

  Pace-Asciak C.R.

  Incubation of homogenates of the rat cerebral cortex with arachidonic acid led to the appearance of hepoxilin A3, analysed as its stable trihydroxy derivative, trioxilin A3, by high resolution gas chromatography/electron impact mass spectrometry. Using the stable deuterium isotope dilution techniq ... >> More

  Incubation of homogenates of the rat cerebral cortex with arachidonic acid led to the appearance of hepoxilin A3, analysed as its stable trihydroxy derivative, trioxilin A3, by high resolution gas chromatography/electron impact mass spectrometry. Using the stable deuterium isotope dilution technique, it is estimated that the cerebral cortex generates 5.0 +/-0.2 ng/mg protein of hepoxilin A3. The formation of this product was stimulated by the addition of exogenous arachidonic acid (12.9 +/-1.5 ng/mg protein) and blocked by boiling of the tissue. Addition of the dual cyclooxygenase/lipoxygenase inhibitor BW 755C at a concentration of 75 microM did not result in a blockade of hepoxilin formation. Three other regions were also tested for their ability to form hepoxilin A3 upon stimulation with exogenous arachidonic acid, i.e. median eminence, 11.7 +/-1.6 ng/mg protein, pituitary, 12.3 +/- 0.7 ng/mg protein; pons, 26.6 +/-0.2 ng/mg protein. In a separate study, 14C-labelled hepoxilin A3 was transformed into 14C-labelled trioxilin A3 by homogenates of the rat whole brain, demonstrating the presence of epoxide hydrolases in the CNS which utilise the hepoxilins as substrates. This is the first demonstration of the occurrence of the hepoxilin pathway in the central nervous system. << Less

  Biochem Biophys Res Commun 151:493-498(1988) [PubMed] [EuropePMC]

• Epoxide hydrolases: their roles and interactions with lipid metabolism.

  Newman J.W., Morisseau C., Hammock B.D.

  The epoxide hydrolases (EHs) are enzymes present in all living organisms, which transform epoxide containing lipids by the addition of water. In plants and animals, many of these lipid substrates have potent biologically activities, such as host defenses, control of development, regulation of infl ... >> More

  The epoxide hydrolases (EHs) are enzymes present in all living organisms, which transform epoxide containing lipids by the addition of water. In plants and animals, many of these lipid substrates have potent biologically activities, such as host defenses, control of development, regulation of inflammation and blood pressure. Thus the EHs have important and diverse biological roles with profound effects on the physiological state of the host organisms. Currently, seven distinct epoxide hydrolase sub-types are recognized in higher organisms. These include the plant soluble EHs, the mammalian soluble epoxide hydrolase, the hepoxilin hydrolase, leukotriene A4 hydrolase, the microsomal epoxide hydrolase, and the insect juvenile hormone epoxide hydrolase. While our understanding of these enzymes has progressed at different rates, here we discuss the current state of knowledge for each of these enzymes, along with a distillation of our current understanding of their endogenous roles. By reviewing the entire enzyme class together, both commonalities and discrepancies in our understanding are highlighted and important directions for future research pertaining to these enzymes are indicated. << Less

  Prog Lipid Res 44:1-51(2005) [PubMed] [EuropePMC]

  This publication is cited by 5 other entries.

• Purification of hepoxilin epoxide hydrolase from rat liver.

  Pace-Asciak C.R., Lee W.S.

  Hepoxilin epoxide hydrolase activity was demonstrated in rat liver cytosol using as substrate [1-14C] hepoxilin A3, a recently described hydroxy epoxide derivative of arachidonic acid. The enzyme was isolated and purified to apparent homogeneity using conventional chromatographic procedures result ... >> More

  Hepoxilin epoxide hydrolase activity was demonstrated in rat liver cytosol using as substrate [1-14C] hepoxilin A3, a recently described hydroxy epoxide derivative of arachidonic acid. The enzyme was isolated and purified to apparent homogeneity using conventional chromatographic procedures resulting in 41-fold purification. The protein eluted during isoelectric focusing at a pI in the 5.3-5.4 range. The specific activity of the purified protein was 1.2 ng/microgram protein/20 min at 37 degrees C. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, under denaturing conditions, a molecular mass value of 53 kDa was observed. Using native polyacrylamide gel electrophoresis, enzyme activity corresponded to the main protein band. The purified protein used hepoxilin A3 as preferred substrate converting it to trioxilin A3. The enzyme was marginally active toward other epoxides such as leukotriene A4 and styrene oxide. The Mr, pI, and substrate specificity of the hepoxilin epoxide hydrolase indicate that this enzyme is different from the recently reported leukotriene A4 hydrolase from human erythrocytes and rat and human neutrophils and constitutes a hitherto undescribed form of epoxide hydrolase with specificity toward hepoxilin A3. Tissue screening for enzyme activity revealed that this enzyme is ubiquitous in the rat. << Less

  J Biol Chem 264:9310-9313(1989) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.