title: Is cytochrome P450 3A4 regulated by menstrual cycle hormones in control endometrium and endometriosis?
abstract: The estrogen-metabolizing activities of cytochrome P450 (CYP) enzymes have been implicated in endometriosis. However, their regulation in various sources of endometrial tissue under different hormonal conditions has not been clarified. Our objective was to study the hormone regulation of a specific CYP enzyme, namely CYP3A4, in control (n = 15) and endometriosis patients (n = 42). To this end, we evaluated mRNA expression (using real-time PCR) of CYP3A4 in tissue samples classified according to the phase of menstrual cycle at which they were obtained as confirmed by the related circulating hormone levels. Protein expression was also evaluated by Western Blot. In order to further investigate the hormonal regulation of CYP3A4, stromal cells from ovarian endometriotic lesions were cultured with the prevailing hormones of the distinct phases of the menstrual cycle. We observed that all control and endometriosis tissues express CYP3A4. Nevertheless, changes in CYP3A4 gene expression related to cycle phase were only seen in the control eutopic endometrium and not in samples from endometriosis patients, with an increase in the luteal phase. Stromal cells isolated from ovarian endometriotic lesions expressed CYP3A4 and their exposure to luteal phase-mimicking hormones (estradiol + progesterone) reduced CYP3A4 mRNA in parallel with a diminished expression of the corresponding receptors, estrogen receptor alpha and progesterone receptor. Our findings suggest that steroid hormones are able to regulate CYP3A4 mRNA expression, although the circulating levels of these hormones can only regulate control endometrium and not endometriosis tissues, probably because of dysregulated local steroid concentration in these latter samples.
authors.affiliation: Hospital Israelita Albert Einstein, 627/701, São Paulo, SP, 05652-900, Brazil. cpiccinato@uwalumni.com.|Department of Gynaecology and Obstetrics, School of Medicine of RibeirãoPreto, Universidade de São Paulo, São Paulo, Brazil. cpiccinato@uwalumni.com.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Piccinato
authors.affiliation: Hospital Israelita Albert Einstein, 627/701, São Paulo, SP, 05652-900, Brazil.|Centro de Endometriose São Paulo, Av. República do Líbano, 460, São Paulo, SP, 04502-000, Brazil.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Neme
authors.affiliation: Hospital Israelita Albert Einstein, 627/701, São Paulo, SP, 05652-900, Brazil.
authors.forename: Natália
authors.initials: N
authors.lastname: Torres
authors.affiliation: Hospital Israelita Albert Einstein, 627/701, São Paulo, SP, 05652-900, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Silvério
authors.affiliation: Hospital Israelita Albert Einstein, 627/701, São Paulo, SP, 05652-900, Brazil.
authors.forename: Vanessa Bitencourt
authors.initials: VB
authors.lastname: Pazzini
authors.affiliation: Department of Gynaecology and Obstetrics, School of Medicine of RibeirãoPreto, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Júlio C
authors.initials: JC
authors.lastname: Rosa E Silva
authors.affiliation: Department of Gynaecology and Obstetrics, School of Medicine of RibeirãoPreto, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Rui A
authors.initials: RA
authors.lastname: Ferriani
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004715:Endometriosis / Q000201:enzymology* / Q000473:pathology; D004717:Endometrium / Q000201:enzymology* / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006801:Humans; D008597:Menstrual Cycle
chemical_list: D012739:Gonadal Steroid Hormones; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP3A4; Cytochrome P450; Endometriosis; Estrogen metabolism; Estrogen-metabolizing enzymes