title: Transport of the soy isoflavone daidzein and its conjugative metabolites by the carriers SOAT, NTCP, OAT4, and OATP2B1.
abstract: Soy isoflavones (IF) are phytoestrogens, which interact with estrogen receptors. They are extensively metabolized by glucuronosyltransferases and sulfotransferases, leading to the modulation of their estrogenic activity. It can be assumed that this biotransformation also has a crucial impact on the uptake of IF by active or passive cellular transport mechanisms, but little is known about the transport of IF phase II metabolites into the cell. Therefore, transport assays for phase II metabolites of daidzein (DAI) were carried out using HEK293 cell lines transfected with five human candidate carriers, i.e., organic anion transporter OAT4, sodium-dependent organic anion transporter (SOAT), Na(+)-taurocholate cotransporting polypeptide (NTCP), apical sodium-dependent bile acid transporter ASBT, and organic anion transporting polypeptide OATP2B1. Cellular uptake was monitored by UHPLC-DAD. DAI monosulfates were transported by the carriers NTCP and SOAT in a sodium-dependent manner, while OAT4-HEK293 cells revealed a partly sodium-dependent transport for these compounds. In contrast, DAI-7,4'-disulfate was only taken up by NTCP-HEK293 cells. DAI-7-glucuronide, but not DAI-4'-glucuronide, was transported exclusively by OATP2B1 in a sodium-independent manner. DAI-7-glucuronide-4'-sulfate, DAI-7-glucoside, and DAI were no substrate of any of the tested carriers. In addition, the inhibitory potency of the DAI metabolites toward estrone-sulfate (E1S) uptake of the above-mentioned carriers was determined. In conclusion, human SOAT, NTCP, OATP2B1, and OAT4 were identified as carriers for the DAI metabolites. Several metabolites were able to inhibit carrier-dependent E1S uptake. These findings might contribute to a better understanding of the bioactivity of IF especially in case of hormone-related cancers.
authors.affiliation: Institute of Pharmacology and Toxicology, JLU Giessen, Giessen, Germany.
authors.forename: Gary
authors.initials: G
authors.lastname: Grosser
authors.affiliation: Institute of Pharmacology and Toxicology, JLU Giessen, Giessen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Döring
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ugele
authors.affiliation: Institute of Pharmacology and Toxicology, JLU Giessen, Giessen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Geyer
authors.affiliation: Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Haid-und-Neu-Straße 9, 76131, Karlsruhe, Germany.
authors.forename: Sabine E
authors.initials: SE
authors.lastname: Kulling
authors.affiliation: Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Haid-und-Neu-Straße 9, 76131, Karlsruhe, Germany. sebastian.soukup@mri.bund.de.
authors.forename: Sebastian T
authors.initials: ST
authors.lastname: Soukup
mesh_terms: D001692:Biological Transport; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D007529:Isoflavones / Q000378:metabolism / Q000493:pharmacokinetics*; D027361:Organic Anion Transporters / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D048789:Phytoestrogens / Q000493:pharmacokinetics*; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*
chemical_list: D007529:Isoflavones; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D048789:Phytoestrogens; C427207:SLC22A11 protein, human; C450859:SLCO2B1 protein, human; D027981:Symporters; C071908:sodium-bile acid cotransporter; C004742:daidzein; D002785:Sterol O-Acyltransferase
keywords: Carrier; Glucuronides; Soy isoflavones; Sulfates; Sulfoglucuronides; Transport