Transport of steroid 3-sulfates and steroid 17-sulfates by the sodium-dependent organic anion transporter SOAT (SLC10A6). Issue 179 (May 2018)

• Record Type: Journal Article
• Authors: Grosser, Gary; Bennien, Josefine; Sánchez-Guijo, Alberto; Bakhaus, Katharina; Döring, Barbara; Hartmann, Michaela; Wudy, Stefan A.; Geyer, Joachim
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 179(2017)
• Page Start: 20
• Page End: 25
• Publication Date: 2018-05
• Subjects: AnDiolS androstenediol sulfate -- AnS androsterone sulfate -- DHEAS dehydroepiandrosterone sulfate -- 16α-OH-DHEAS 16α--hydroxydehydroepiandrosterone sulfate -- DHTS 5α-dihydrotestosterone sulfate -- epiAnS epiandrosterone sulfate -- eTS epitestosterone sulfate -- E1S estrone-3-sulfate -- E2-3S 17β-estradiol-3-sulfate -- E2-17S 17β-estradiol-17-sulfate -- E2-diS 17β-estradiol-3, 17-disulfate -- IS internal standard -- LC liquid chromatography -- LOQ limit of quantification -- MS mass spectrometry -- PBS phosphate-buffered saline -- PregS pregnenolone sulfate -- 17α-OH-PregS 17-hydroxypregnenolone sulfate -- SOAT sodium-dependent organic anion transporter -- TS testosterone sulfate; SOAT -- SLC10A6 -- Transport -- Sulfated steroids -- 17β-Estradiol-17-sulfate -- 17β-Estradiol-3, 17-disulfate -- Epiandrosterone sulfate; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2017.09.013
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: SOAT transports the 3'-monosulfates 17α-OH-PREGS, androsterone sulfate, and epiandrosterone sulfate. SOAT transports the 17'-monosulfates 17β-estradiol-17-sulfate, testosterone sulfate (TS), epi-TS, and 5α-dihydro-TS. The 3'- and 17'-monosulfate groups of the SOAT substrates have flexibility for α- or β-orientation. SOAT has no transport activity for 17β-estradiol-3, 17-disulfate, although this steroid is an inhibitor of SOAT. Abstract: The sodium-dependent organic anion transporter SOAT/Soat shows highly specific transport activity for sulfated steroids. SOAT substrates identified so far include dehydroepiandrosterone sulfate, 16α-hydroxydehydroepiandrosterone sulfate, estrone-3-sulfate, pregnenolone sulfate, 17β-estradiol-3-sulfate, and androstenediol sulfate. Apart from these compounds, many other sulfated steroids occur in mammals. Therefore, we aimed to expand the substrate spectrum of SOAT and analyzed the SOAT-mediated transport of eight different sulfated steroids by combining in vitro transport experiments in SOAT-transfected HEK293 cells with LC–MS/MS analytics of cell lysates. In addition, we aimed to better understand the structural requirements for SOAT substrates and so selected structural pairs varying only at specific positions: 3α/3β-sulfate, 17α/17β-sulfate, mono-sulfate/di-sulfate, and 17α-hydroxylation. We found significant and sodium-dependent SOAT-mediated transport of 17α-hydroxypregnenolone sulfate, 17β-estradiol-17-sulfate, androsterone sulfate, epiandrosterone sulfate, testosterone sulfate, epitestosterone sulfate, and 5α-dihydrotestosterone sulfate. However, 17β-estradiol-3, 17-disulfate was not transported by SOAT. In conclusion: SOAT substrates from the group of sulfated steroids are characterized by a planar and lipophilic steroid backbone in trans-trans - trans conformation of the rings and a negatively charged mono-sulfate group at positions 3′ or 17′ with flexibility for α- or β- orientation. Furthermore, 5α-reduction, 16α-hydroxylation, and 17α-hydroxylation are acceptable for SOAT substrate recognition, whereas addition of a second negatively charged sulfate group seems to abolish substrate binding to SOAT, and so 17β-estradiol-3, 17-disulfate is not transported by SOAT.