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

Abstract

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.

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

“…In this regard, a potential role of EPHX1 in reproductive physiology was suggested previously. EPHX1 is expressed in ovarian follicle cells ( Cannady et al, 2002 ) and is regulated by progesterone during the menstrual cycle ( Popp et al, 2010 ). Several endogenous biologically active epoxide mediators of the steroidogenic pathway were found to be EPHX1 substrates, such as androstene oxide (16α,17α-epoxyandrosten-3-one) and estroxide (epoxyestratrienol) ( Vogel-Bindel et al, 1982 ).…”

Microsomal epoxide hydrolase 1 (EPHX1): Gene, structure, function, and role in human disease

“…Interestingly, in regard to systemic hormonal regulation, a study in primary cultured rat hepatocytes demonstrated that insulin positively and glucagon negatively regulate EPHX1 expression (Kim et al 2003) while progesterone was later shown to regulate EPHX1 expression in the endometrium during menstrual cycle (Popp et al 2010). However, the relevance of these observations for human physiology remains to be elucidated.…”

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

“…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]. Alternatively, over the last decade, mEH was also described as mediating the transport of bile acid in the liver [26],[27].…”