Metabolism of Monoepoxides of Methyl Linoleate: Bioactivation and Detoxification

Greene, Jessica F.; Williamson, Kristin C.; Newman, John W.; Morisseau, Christophe; Hammock, Bruce D.

doi:10.1006/abbi.2000.1753

Cited by 47 publications

(49 citation statements)

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“…However, while human leukocytes express a fatty acid ester synthase activity (Wright et al 1987) and fatty acid methyl esters have been detected in a physiological context (Schmidt et al 1996), no studies have demonstrated that methyl esters of the DiHOMEs are synthesized in vivo in a physiological context. In contrast, when the methyl ester is administered to Sf-21 cells, the methyl moiety is cleaved and only the free DiHOMEs are detected (Greene et al 2000b). This suggests that the efficacy of methyl 9,10-/12,13-DiHOME, but not the corresponding acid, in respiratory burst inhibition is attributable to the ability of the uncharged ester to readily translocate across the cytoplasmic membrane.…”

Section: Discussionmentioning

confidence: 97%

“…Dibutyryl cyclic adenosine monophosphate (AMP) was dissolved as a stock solution in 9:1 ethanol:water which was stored at −70°C for no longer than 2-3 months (loss of activity was observed on prolonged storage). A mixture of methyl 9(10)-EpOME and 12(13)-EpOME was synthesized as described (Greene et al 2000b); a mixture of methyl 5(6), 8(9), 11(12), and 14(15)-epoxyeicosatrienoates (EpETEs) was synthesized in an analogous fashion. Methyl, propyl, and butyl esters of stearic acid were synthesized as described (Greene et al 2000a).…”

Section: Reagentsmentioning

confidence: 99%

“…Methyl, propyl, and butyl esters of stearic acid were synthesized as described (Greene et al 2000a). [10][11][12] were synthesized by acidic hydrolysis of methyl 9(10)-EpOME and 12(13)-EpOME as described (Greene et al 2000b);methyl 5,6-, 8,9-, 11,12-, and 14,15-DiHET were synthesized in an analogous fashion. Methyl 5,8,11,and 14,15-DiHET were purified by reverse-phase HPLC (Brownlee Spheri-5 250×4.6 RP-18 column, 1 ml/min, acetonitrile:water:acetic acid from 40: 60:0.1 to 55:45:0.1 in 7.1 min; to 65:35:0.1 in 12.5 min; to 74:26:0.1 in 22 min).…”

Section: Reagentsmentioning

confidence: 99%

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Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst

Hammock

2007

J Biosci

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The leukotoxins [9(10)-and 12(13)-EpOME] are produced by activated inflammatory leukocytes such as neutrophils. High EpOME levels are observed in disorders such as acute respiratory distress syndrome and in patients with extensive burns. Although the physiological significance of the EpOMEs remains poorly understood, in some systems, the EpOMEs act as a protoxin, with their corresponding epoxide hydrolase metabolites, 9,10-and 12,13-DiHOME, specifically exerting toxicity. Both the EpOMEs and the DiHOMEs were also recently shown to have neutrophil chemotactic activity. We evaluated whether the neutrophil respiratory burst, a surge of oxidant production thought to play an important role in limiting certain bacterial and fungal infections, is modulated by members of the EpOME metabolic pathway. We present evidence that the DiHOMEs suppress the neutrophil respiratory burst by a mechanism distinct from that of respiratory burst inhibitors such as cyclosporin H or lipoxin A4, which inhibit multiple aspects of neutrophil activation.

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Section: Discussionmentioning

confidence: 97%

Section: Reagentsmentioning

confidence: 99%

Section: Reagentsmentioning

confidence: 99%

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Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst

Hammock

2007

J Biosci

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“…However, assuming that dihydroxy lipid phosphates are the endogenous substrates for the sEH phosphatase domain, it would be logical for this activity to be associated with the physiological effects of fatty acid epoxides. In particular, these compounds may be responsible for a portion of the reported fatty acid diol-dependent biology (11,38,39 …”

Section: Discussionmentioning

confidence: 99%

“…Epoxy fatty acids generated by cytochrome P450 epoxygenases are endogenous substrates for the sEH C-terminal domain (5), with critical roles in the regulation of cardiovascular, renal, and inflammatory biology (6)(7)(8)(9). The hydrolysis of epoxy fatty acids modulates their intracellular fate (10,11) and biological activity (9,12,13). In vivo, the pharmacological blockade of epoxide hydrolysis attenuates hypertension (4,14), whereas the deletion of this gene reduces blood pressure in male mice to female levels (15).…”

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confidence: 99%

The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity

Newman

Morisseau

Harris

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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192

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The gene EPXH2 encodes for the soluble epoxide hydrolase (sEH), an enzyme involved in the regulation of cardiovascular and renal physiology containing two distinct domains connected via a proline-rich linker. The C-terminal domain containing the EH catalytic activity has been well studied. In contrast, a function for the N-terminal domain, which has high homology to the haloacid dehalogenase family of phosphatases, has not been definitively reported. In this study we describe the N-terminal domain as a functional phosphatase unaffected by a number of classic phosphatase inhibitors. Assuming a functional association between these catalytic activities, dihydroxy lipid phosphates were rationalized as potential endogenous substrates. A series of phosphorylated hydroxy lipids were therefore synthesized and found to be excellent substrates for the human sEH. The best substrate tested was the monophosphate of dihydroxy stearic acid (threo-9͞ 10-phosphonoxy-hydroxy-octadecanoic acid) with K m ‫؍‬ 21 ؎ 0.3 M, VMax ‫؍‬ 338 ؎ 12 nmol⅐min ؊1 ⅐mg ؊1 , and kcat ‫؍‬ 0.35 ؎ 0.01 s ؊1 . Therefore dihydroxy lipid phosphates are possible candidates for the endogenous substrates of the sEH N-terminal domain, which would represent a novel branch of fatty acid metabolism with potential signaling functions.T he soluble epoxide hydrolase (sEH), first described in 1972(1), is an ubiquitous enzyme in vertebrates that transforms epoxides to their corresponding diols (2). Although uniformly expressed in the liver, high expression of sEH is highly localized in other tissues including vascular endothelium, some smooth muscle, and the proximal tubule (3, 4). Epoxy fatty acids generated by cytochrome P450 epoxygenases are endogenous substrates for the sEH C-terminal domain (5), with critical roles in the regulation of cardiovascular, renal, and inflammatory biology (6-9). The hydrolysis of epoxy fatty acids modulates their intracellular fate (10, 11) and biological activity (9,12,13). In vivo, the pharmacological blockade of epoxide hydrolysis attenuates hypertension (4, 14), whereas the deletion of this gene reduces blood pressure in male mice to female levels (15).The sEH is a homodimer with a monomeric unit of 62.5 kDa (2) whose primary structure suggests that the EPXH2 gene was produced by the fusion of two primordial dehalogenase genes (16,17). This gene fusion hypothesis was recently supported by a 2.8-Å resolution x-ray crystal structure of the mouse enzyme (18). The C-terminal sEH domain has high homology to haloalkane dehalogenase, whereas the N-terminal domain is similar to haloacid dehalogenase (HAD). Although analysis of the sEH crystal structure revealed that the conserved HAD-like catalytic residues were properly oriented for catalysis, no dehalogenase activity was detected (18). However, the amino-terminal catalytic DXDX(T͞V) motif of HAD has been used to describe an enzyme class that includes numerous phosphatases (19)(20)(21).It can be argued that gene fusion events are driven by evolution, leading to the physical linkage of f...

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Measurement of Soluble Epoxide Hydrolase (sEH) Activity

2007

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The human soluble epoxide hydrolase (sEH; EC 3.3.3.2) is the product of the EXPH2 gene. The sEH catalyzes the addition of a water molecule to an epoxide, resulting in the corresponding diol. Early work suggested a role of sEH in detoxifying a wide array of xenobiotic epoxides; however, recent findings clearly implicate the sEH in the regulation of blood pressure, pain, and inflammation through the hydrolysis of endogenous epoxy fatty acids such as epoxyeicosatrienoic acids (EETs). Both expression and activity of sEH are influenced by a wide array of xenobiotics, underlying how environmental contaminants could influence human health through sEH. This unit describes radiometric, fluorimetric, and mass spectrometric assays for measuring the activity of sEH and its inhibition.

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Metabolism of Monoepoxides of Methyl Linoleate: Bioactivation and Detoxification

Cited by 47 publications

References 61 publications

Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst

Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst

The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity

Measurement of Soluble Epoxide Hydrolase (sEH) Activity

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