Involvement of Pituitary Hormone in the Sex-Related Regulation of Hepatic Epoxide Hydrolase Activity in Mice.

Inoue, Naoto; Fujiwara, Kiyomi; Iwata, Toru; Imai, Kunihiko; Aimoto, Tachio

doi:10.1248/bpb.18.536

Cited by 6 publications

(5 citation statements)

References 1 publication

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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%

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%

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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“…Vertebrate EPHX2 is an inducible gene product and a number of studies have demonstrated hormonal regulation (Denlinger and Vesell, 1989;Inoue et al, 1993;Inoue et al, 1995;Pinot et al, 1995). For example, hepatic EPHX2 enzyme activity in mice is under the control of the hypothalamic-pituitary-gonadal axis (Inoue et al, 1995). In the present study, we demonstrate for the first time that rhesus macaque EPHX2 gene expression is regulated by the luteotropic hormone LH.…”

Section: Discussionsupporting

confidence: 56%

“…large luteal, small luteal, stromal and endothelial cells) within the rhesus macaque CL. Vertebrate EPHX2 is an inducible gene product and a number of studies have demonstrated hormonal regulation (Denlinger and Vesell, 1989;Inoue et al, 1993;Inoue et al, 1995;Pinot et al, 1995). For example, hepatic EPHX2 enzyme activity in mice is under the control of the hypothalamic-pituitary-gonadal axis (Inoue et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Dynamic expression of epoxyeicosatrienoic acid synthesizing and metabolizing enzymes in the primate corpus luteum

Irusta

Murphy

Perez

et al. 2007

MHR: Basic Science of Reproductive Medicine

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Epoxyeicosatrienoic acids (EpETrEs), produced from arachidonic acid via cytochrome P450 (CYP) epoxygenases, regulate inflammation, angiogenesis, cellular proliferation, ion transport and steroidogenesis. EpETrE actions are regulated through their metabolism to diols (dihydroxyeicosatrienoic acids; DiHETrE) via the enzyme soluble epoxide hydrolase (EPHX2). We set out to determine, therefore, whether EpETrE generating (epoxygenases CYP2C8, 2C9, 2C19, 2J2, 1A2 and 3A4) and metabolizing (EPHX2) enzymes are expressed in the primate corpus luteum (CL). CL were isolated from rhesus macaques during the early (day 3-5 post-LH surge), mid (day 6-8), mid-late (day 10-12), late (day 14-16) and very-late (day 17-19: menses) luteal phase of natural menstrual cycles. EPHX2 mRNA levels peaked in mid-late CL (5-fold when compared with early CL, P<0.05) and remained elevated in the late CL. Ablation of pituitary LH secretion and luteal steroid synthesis significantly reduced (P<0.05) EPHX2 mRNA levels in the mid-late CL, with progestin replacement being insufficient to restore its level of expression to control values. EPHX2 protein was localized to large and small luteal cells, as well as vascular endothelial cells. The EpETrE-generating CYP epoxygenase 2J2, 2C9 and 3A4 genes were also expressed in the macaque CL. While CYP2J2 mRNA levels did not significantly change through the luteal phase, CYP2C9 and CYP3A4 levels were significantly (P<0.05) higher in the mid-late phase when compared with the early phase. CYP2C9, 2J2 and 3A4 proteins were each localized to the large luteal cells, with 2C9 and 2J2 also being present in the small luteal, stromal and endothelial cells. These studies demonstrate for the first time that an EpETrE generating and metabolizing system exists in the primate CL, with the latter being regulated by LH and steroid hormone(s).

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“…A number of studies suggested that sEH activity is under a direct influence of sexual hormone regulation (35,36). In rodents, liver and kidney sEH specific activity was elevated in males compared with females (35,36,53).…”

Section: Discussionmentioning

confidence: 99%

Alteration in plasma testosterone levels in male mice lacking soluble epoxide hydrolase

Luria¹,

Morisseau²,

Tsai³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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Soluble epoxide hydrolase (Ephx2, sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH(2)-terminal phosphatase activities. sEH converts epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), and the phosphatase activity is suggested to be involved in cholesterol metabolism. EETs participate in a wide range of biological functions, including regulation of vascular tone, renal tubular transport, cardiac contractility, and inflammation. Inhibition of sEH is a potential approach for enhancing the biological activity of EETs. Therefore, disruption of sEH activity is becoming an attractive therapeutic target for both cardiovascular and inflammatory diseases. To define the physiological role of sEH, we characterized a knockout mouse colony lacking expression of the Ephx2 gene. Lack of sEH enzyme is characterized by elevation of EET to DHET ratios in both the linoleate and arachidonate series in plasma and tissues of both female and male mice. In male mice, this lack of expression was also associated with decreased plasma testosterone levels, sperm count, and testicular size. However, this genotype was still able to sire litters. Plasma cholesterol levels also declined in this genotype. Behavior tests such as anxiety-like behavior and hedonic response were also examined in Ephx2-null and WT mice, as all can be related to hormonal changes. Null mice showed a level of anxiety with a decreased hedonic response. In conclusion, this study provides a broad biochemical, physiological, and behavioral characterization of the Ephx2-null mouse colony and suggests a mechanism by which sEH and its substrates may regulate circulating levels of testosterone through cholesterol biosynthesis and metabolism.

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Involvement of Pituitary Hormone in the Sex-Related Regulation of Hepatic Epoxide Hydrolase Activity in Mice.

Cited by 6 publications

References 1 publication

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

Dynamic expression of epoxyeicosatrienoic acid synthesizing and metabolizing enzymes in the primate corpus luteum

Alteration in plasma testosterone levels in male mice lacking soluble epoxide hydrolase

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