Differential regulation of soluble epoxide hydrolase by clofibrate and sexual hormones in the liver and kidneys of mice

Pinot, Franck; Grant, David F.; Spearow, Jimmy L.; Parker, Anthony G.; Hammock, Bruce D.

doi:10.1016/0006-2952(95)00167-x

Cited by 58 publications

(59 citation statements)

References 45 publications

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“…Immunoblot analysis of sEH protein levels in kidney cytosolic fractions was also performed. Consistent with previous reports (32,33), renal sEH mRNA expression levels were higher for male versus female wild-type mice (Fig. 5).…”

Section: Generation and Characterization Of Seh-nullsupporting

confidence: 93%

“…The development and use of such compounds to achieve selective sEH inhibition in vivo has been demonstrated by Hammock and co-workers (40). A number of hypolipidemic compounds, which are also peroxisome proliferators, induce the expression of renal sEH (33,41,42). This may have important implications in drug therapy, particularly for patients at risk for the development of hypertension.…”

Section: Table I Arachidonic Acid Metabolism By Kidney S-9 Fractions mentioning

confidence: 99%

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Targeted Disruption of Soluble Epoxide Hydrolase Reveals a Role in Blood Pressure Regulation

Sinal¹,

Miyata²,

Tohkin³

et al. 2000

Journal of Biological Chemistry

316

270

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Renal microsomal cytochrome P-450 monooxygenasedependent metabolism of arachidonic acid generates a series of regioisomeric epoxyeicosatrienoic acids that can be further metabolized by soluble epoxide hydrolase to the corresponding dihydroxyeicosatrienoic acids. Evidence exists that these metabolites affect renal function and, in particular, blood pressure regulation. To examine this possibility, blood pressure and renal arachidonic acid metabolism were examined in mice with a targeted disruption of the soluble epoxide hydrolase gene. Systolic blood pressure of male soluble epoxide hydrolase-null mice was lower compared with wild-type mice in both the absence and presence of dietary salt loading. Both female soluble epoxide hydrolase-null and wild-type female mice also had significantly lower systolic blood pressure than male wild-type mice. Renal formation of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids was markedly lower for soluble epoxide hydrolase-null versus wild-type mice of both sexes. Although disruption of soluble epoxide hydrolase in female mice had minimal effects on blood pressure, deletion of this gene feminized male mice by lowering systolic blood pressure and altering arachidonic acid metabolism. These data provide the first direct evidence for a role for soluble epoxide hydrolase in blood pressure regulation and identify this enzyme as a novel and attractive target for therapeutic intervention in hypertension. Mammalian soluble epoxide hydrolase (sEH)1 is a cytosolic enzyme expressed in multiple tissues that catalyzes the conversion of a diverse group of epoxides to their corresponding diols (1, 2). The broad spectrum of xenobiotic epoxides metabolized by this enzyme suggests a role in the protection of cells against the potentially harmful effects of these compounds (3). However, sEH hydrates fatty acid epoxides most effectively, with epoxides of arachidonic acid (AA) being among the best substrates (4 -6). This metabolism may result in the formation of metabolites with greater or less biological activity, indicating that sEH may have important physiological functions. Intracellular metabolism of AA by prostaglandin H2 synthase, lipoxygenases, and the cytochrome P-450 (CYP) monooxygenase system generates a number of metabolites, collectively termed eicosanoids, with important biological and cell signaling roles (7-12). CYP-dependent metabolism of AA (Fig. 1) generates three primary classes of metabolites: mid-chain cis-trans-conjugated dienols (5-, 8-, 9-, 11-, 12-and 15-hydroxyeicosatetraenoic acids (HETEs)); -terminal alcohols (16-through 20-hydroxyeicosatetraenoic acids); and, cis-epoxyeicosatrienoic acids (6-, 8,9-, 11,12-, and 14,15 epoxyeicosatrienoic acids (EETs)) (13). EETs have been shown in vitro to be efficiently hydrated to their corresponding dihydroxyeicosatrienoic acids (DHETs) by sEH (5).Evidence exists for a variety of renal functions attributable to EETs and DHETs generated by CYP-dependent epoxygenase activity and sEH, respectively. Most notably, evidence exists for ...

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Section: Generation and Characterization Of Seh-nullsupporting

confidence: 93%

Section: Table I Arachidonic Acid Metabolism By Kidney S-9 Fractions mentioning

confidence: 99%

Targeted Disruption of Soluble Epoxide Hydrolase Reveals a Role in Blood Pressure Regulation

Sinal¹,

Miyata²,

Tohkin³

et al. 2000

Journal of Biological Chemistry

316

270

View full text Add to dashboard Cite

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“…Blots were then blocked in 5% dry milk and incubated at 4°C overnight with a primary rabbit anti-sEH antibody. 11,15,16 Signal was visualized using a biotinylated secondary antibody (Amersham) with an ECL plus chemiluminescence detection kit (Amersham). Autoradiograms were scanned and band optical densities quantified with QuantityOne software (BioRad).…”

Section: Western Blot and Immunohistochemistrymentioning

confidence: 99%

Soluble Epoxide Hydrolase Gene Deletion Is Protective Against Experimental Cerebral Ischemia

Zhang

Otsuka

Sugo

et al. 2008

Stroke

157

177

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Background and Purpose-Cytochrome P450 epoxygenase metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs). EETs are produced in the brain and perform important biological functions, including vasodilation and neuroprotection. However, EETs are rapidly metabolized via soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). We tested the hypothesis that sEH gene deletion is protective against focal cerebral ischemia through enhanced collateral blood flow. Methods-sEH knockout (sEHKO) mice with and without EETs antagonist 14, 15 epoxyeicosa-5(Z)-enoic acid (EEZE) were subjected to 2-hour middle cerebral artery occlusion (MCAO), and infarct size was measured at 24 hours of reperfusion and compared to wild-type (WT) mice. Local CBF rates were measured at the end of MCAO using iodoantipyrine (IAP) autoradiography, sEH protein was analyzed by Western blot and immunohistochemistry, and hydrolase activity and levels of EETs/DHETs were measured in brain and plasma using LC-MS/MS and ELISA, respectively. Results-sEH immunoreactivity was detected in WT, but not sEHKO mouse brain, and was localized to vascular and nonvascular cells. 14,15-DHET was abundantly present in WT, but virtually absent in sEHKO mouse plasma. However, hydrolase activity and free 14,15-EET in brain tissue were not different between WT and sEHKO mice. Infarct size was significantly smaller, whereas regional cerebral blood flow rates were significantly higher in sEHKO compared to WT mice. Infarct size reduction was recapitulated by 14,15-EET infusion. However, 14,15-EEZE did not alter infarct size in sEHKO mice. Conclusions-sEH gene deletion is protective against ischemic stroke by a vascular mechanism linked to reduced hydration of circulating EETs.

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“…Rat renal CYP2C23 has also been shown to be inducible by fibrates (Muller et al, 2004), whereas rat hepatic CYP2C11 and CYP2C12, but not CYP2C13, are repressed (Corton et al, 1998). Hepatic and renal sEH expression in rodents is also induced after treatment with clofibrate (Pinot et al, 1995).…”

mentioning

confidence: 99%

Cytochrome P450 Eicosanoids are Activators of Peroxisome Proliferator-Activated Receptor α

et al. 2007

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ABSTRACT:Cytochrome P450 (P450) eicosanoids regulate vascular tone, renal tubular transport, cellular proliferation, and inflammation. Both the CYP4A -hydroxylases, which catalyze 20-hydroxyeicosatetraenoic acid (20-HETE) formation, and soluble epoxide hydrolase (sEH), which catalyzes epoxyeicosatrienoic acid (EET) degradation to the dihydroxyeicosatrienoic acids (DHETs), are induced upon activation of peroxisome proliferator-activated receptor ␣ (PPAR␣) by fatty acids and fibrates. In contrast, the CYP2C epoxygenases, which are responsible for EET formation, are repressed after fibrate treatment. We show here that P450 eicosanoids can bind to and activate PPAR␣ and result in the modulation of PPAR␣ target gene expression. In transactivation assays, 14,15-DHET, 11,2-EET, and 20-HETE were potent activators of PPAR␣. Gel shift assays showed that EETs, DHETs, and 20-HETE induced PPAR␣-specific binding to its cognate response element. Expression of apolipoprotein A-I was decreased 70% by 20-HETE, whereas apolipoprotein A-II expression was increased up to 3-fold by 11,12-EET, 14,15-DHET, and 20-HETE. In addition, P450 eicosanoids induced CYP4A1, sEH, and CYP2C11 expression, suggesting that they can regulate their own levels. Given that P450 eicosanoids have multiple cardiovascular effects, pharmacological modulation of their formation and/or degradation may yield therapeutic benefits.

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Differential regulation of soluble epoxide hydrolase by clofibrate and sexual hormones in the liver and kidneys of mice

Cited by 58 publications

References 45 publications

Targeted Disruption of Soluble Epoxide Hydrolase Reveals a Role in Blood Pressure Regulation

Targeted Disruption of Soluble Epoxide Hydrolase Reveals a Role in Blood Pressure Regulation

Soluble Epoxide Hydrolase Gene Deletion Is Protective Against Experimental Cerebral Ischemia

Cytochrome P450 Eicosanoids are Activators of Peroxisome Proliferator-Activated Receptor α

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