Microsomal epoxide hydrolase of rat liver is a subunit of theanti-oestrogen-binding site

Mésange, Fabienne; Sebbar, Mohamed; Kedjouar, Blandine; Capdevielle, Joël; Guillemot, Jean‐Claude; Ferrara, Pascual; Bayard, Françis; Delarue, Frédéric; Faye, Jean-Charles; Poirot, Marc

doi:10.1042/bj3340107

Cited by 28 publications

(31 citation statements)

References 44 publications

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“…For this reason, the liver have been chosen for the purification of the AEBS but the pharmacological profiles of the AEBS found in the liver and in tumor cell lines such as MCF-7 cells (a mam-mary adenocarcinoma cell line) have been reported to be different, suggesting a possible difference in the composition of the AEBS in the two systems (19). We have recently reported that the AEBS from rat liver was a hetero-oligomeric multiprotein complex that contained subunits that were not directly involved in the binding of tamoxifen such as the microsomal epoxide hydrolase (mEH) (20), the carboxyl-esterase (ES-10), and the liver fatty acid-binding protein (FABP) (21). Each of these proteins have been implicated in lipid metabolism: mEH is a bile acid transporter (22), and carboxylesterase has cholesterol esterification properties (23) but were related to the AEBS found in normal liver because ES-10 and FABP were not found in tumor cell lines.…”

Section: -[4-(12-diphenyl-1-butenyl)-phenoxy]-nn-dimethylethanaminementioning

confidence: 99%

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Molecular Characterization of the Microsomal Tamoxifen Binding Site

Kedjouar

Médina

Oulad-Abdelghani

et al. 2004

Journal of Biological Chemistry

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108

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Tamoxifen is a selective estrogen receptor modulator widely used for the prophylactic treatment of breast cancer. In addition to the estrogen receptor (ER), tamoxifen binds with high affinity to the microsomal antiestrogen binding site (AEBS), which is involved in ERindependent effects of tamoxifen. In the present study, we investigate the modulation of the biosynthesis of cholesterol in tumor cell lines by AEBS ligands. As a consequence of the treatment with the antitumoral drugs tamoxifen or PBPE, a selective AEBS ligand, we show that tumor cells produced a significant concentration-and time-dependent accumulation of cholesterol precursors. Sterols have been purified by HPLC and gas chromatography, and their chemical structures determined by mass spectrometric analysis. The major metabolites identified were 5␣-cholest-8-en-3␤-ol for tamoxifen treatment and 5␣-cholest-8-en-3␤-ol and cholesta-5,7-dien-3␤-ol, for PBPE treatment, suggesting that these AEBS ligands affect at least two enzymatic steps: the 3␤-hydroxysterol-⌬ Tamoxifen is a selective estrogen receptor modulator (SERM) widely used for the treatment and the prevention of breast cancer (1). More than 20 years ago, Sutherland et al. (2) discovered that tamoxifen bound to a high affinity binding site that was different from the estrogen receptor (2). This site has been named the microsomal antiestrogen binding site (AEBS) 1 because it is localized in the microsomes of cells; it binds principally aryl aminoethoxy antiestrogens and has no affinity for estrogens (3). Two classes of selective ligands have been developed so far to selectively target the AEBS. The first class includes diphenylmethane derivatives of tamoxifen (DPPE) and N-pyrrolidino-2-[4-(benzyl)-phenoxy-ethanamine⅐HCl (PBPE) (4 -6), while the second class includes oxygenated derivatives of cholesterol such as 7-ketocholestanol (7-9). We and others (5, 10 -14) have shown that AEBS ligands inhibit the growth of tumor cell lines in vitro and in vivo, demonstrating that the AEBS was involved in the mediation of the effects of these structural classes of its cognate ligands. These compounds represent not only specific tools to study AEBS function but are also anticancer drug candidates because the selective AEBS ligand DPPE (Tesmilifene) was brought up to phase II and III clinical trials for the treatment of breast and prostate cancer in association with doxorubicin (15-17). Two principal points remained unsolved: the first is the precise molecular nature of the AEBS and the second the explanation of the difference observed between the nanomolar affinity of AEBS ligands and their micromolar effectiveness for growth control and cytotoxicity.We have been involved in the identification of the AEBS for several years. The AEBS can be found in most tissues in mammals and is abundant in microsomes of liver that contained 20 -30ϫ the amount found in tumor cell lines (18). For this reason, the liver have been chosen for the purification of the AEBS but the pharmacological profiles of the AEBS found in the ...

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Section: -[4-(12-diphenyl-1-butenyl)-phenoxy]-nn-dimethylethanaminementioning

confidence: 99%

“…Cells were homogenized by 6 successive freeze/thaw cycles and microsomal fractions prepared as described earlier (20). Binding experiments were conducted as described previously (6).…”

Section: Chemicals-pbpe Dppe N-morpholino-2-[4-(benzyl)-phenoxy]-etmentioning

confidence: 99%

Molecular Characterization of the Microsomal Tamoxifen Binding Site

Kedjouar

Médina

Oulad-Abdelghani

et al. 2004

Journal of Biological Chemistry

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108

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“…A potential role of mEH in sexual development is supported by the fact that androstene oxide is a very good mEH substrate [19], and that mEH is an apparent subunit of the anti-oestrogen-binding site [20] Such a role could be related to the observed relation between mEH polymorphism and spontaneous abortion [21] or preeclampsia [22]. Furthermore, mEH is well expressed in follicle cells in the ovaries [23],[24], and its expression is regulated by progesterone during the menstrual cycle [25].…”

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confidence: 99%

Development of fluorescent substrates for microsomal epoxide hydrolase and application to inhibition studies

Morisseau¹,

Bernay²,

Escaich³

et al. 2011

Analytical Biochemistry

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The microsomal epoxide hydrolase (mEH) plays a significant role in the metabolism of numerous xenobiotics. Additionally, it has a potential role in sexual development and bile acid transport, and it is associated with a number of diseases, such as emphysema, spontaneous abortion, eclampsia and several forms of cancer. Toward developing chemical tools to study mEH biological role, we designed and synthesized a series of absorbent and fluorescent substrates. The highest activity for both rat and human mEH was obtained with the fluorescent substrate cyano(6-methoxy-naphthalen-2-yl)methyl glycidyl carbonate (11). An in vitro inhibition assay using this substrate ranked a series of known inhibitors similarly to the assay that used radioactive cis-stilbene oxide, but with a greater discrimination between inhibitors. These results demonstrate that the new fluorescence-based assay is a useful tool for the discovery of structure-activity relationships among mEH inhibitors. Further, this substrate could also be used for the screening chemical library with high accuracy and with a Z' value about 0.7. This new assay permits a significant decrease in labor and cost as well as offering the advantage of a continuous readout. However, it should not be used with crude enzyme preparations due to interfering reactions.

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“…It is mainly involved in the metabolic activation or detoxification of epoxides (Guengerich 1994). Besides, it is known that mEH is a subunit of the AEBS complex (Mesange et al 1998;2002). Furthermore, it may function as a useful marker for the overall prognosis during endocrine treatment of breast cancer patients with tamoxifen, due to the significant correlation of high mEH expression and a poor disease outcome .…”

Section: Discussionmentioning

confidence: 99%

Microsomal epoxide hydrolase expression in the endometrial uterine corpus is regulated by progesterone during the menstrual cycle

et al. 2010

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We have shown previously that high expression levels of microsomal epoxide hydrolase (mEH) correlate with a poor prognosis of breast cancer patients receiving tamoxifen, suggesting that enhanced mEH expression could lead to antiestrogen resistance (Fritz et al. in J Clin Oncol 19:3-9, 2001). Thus, the purpose of this study was to gain insights into the role of mEH in hormone-responsive tissues. We analyzed biopsy samples of the endometrium by immunohistochemical staining, pointing to a regulation of mEH during the menstrual cycle: during the first half mEH expression was low, increased during the second half and reached highest levels during pregnancy. Additionally, the progesterone receptor (PR) positive human endometrial cell lines IKPRAB-36 (estrogene receptor alpha [ERalpha] negative) and ECC1-PRAB72 (ERalpha positive) were chosen to further investigate the hormonal regulation of mEH expression. Western Blot and quantitative RT-PCR analysis revealed an increase of mEH expression after treatment with medroxy-progesterone 17-acetate (MPA) in the ERalpha containing ECC1-PRAB72 cells. In contrast our results suggest that MPA had no influence on the mEH protein level in the ERalpha- IKPRAB-36 cells. In conclusion, mEH expression is regulated by progesterone in the presence of both PRs and ERalpha.

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Microsomal epoxide hydrolase of rat liver is a subunit of theanti-oestrogen-binding site

Cited by 28 publications

References 44 publications

Molecular Characterization of the Microsomal Tamoxifen Binding Site

Molecular Characterization of the Microsomal Tamoxifen Binding Site

Development of fluorescent substrates for microsomal epoxide hydrolase and application to inhibition studies

Microsomal epoxide hydrolase expression in the endometrial uterine corpus is regulated by progesterone during the menstrual cycle

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