title: Deconjugation of soy isoflavone glucuronides needed for estrogenic activity.
abstract: Soy isoflavones (SIF) are present in the systemic circulation as conjugated forms of which the estrogenic potency is not yet clear. The present study provides evidence that the major SIF glucuronide metabolites in blood, genistein-7-O-glucuronide (GG) and daidzein-7-O-glucuronide (DG), only become estrogenic after deconjugation. The estrogenic potencies of genistein (Ge), daidzein (Da), GG and DG were determined using stably transfected U2OS-ERα, U2OS-ERβ reporter gene cells and proliferation was tested in T47D-ERβ cells mimicking the ERα/ERβ ratio of healthy breast cells and inT47D breast cancer cells. In all assays applied, the estrogenic potency of the aglycones was significantly higher than that of their corresponding glucuronides. UPLC analysis revealed that in U2OS and T47D cells, 0.2-1.6% of the glucuronides were deconjugated to their corresponding aglycones. The resulting aglycone concentrations can account for the estrogenicity observed upon glucuronide exposure. Interestingly, under similar experimental conditions, rat breast tissue S9 fraction was about 30 times more potent in deconjugating these glucuronides than human breast tissue S9 fraction. Our study confirms that SIF glucuronides are not estrogenic as such, and that the small % of deconjugation in the cell is enough to explain the slight bioactivity observed for the SIF-glucuronides. Species differences in deconjugation capacity should be taken into account when basing risk-benefit assessment of these SIF for the human population on animal data.
authors: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands. Electronic address: arif.sau.agch@gmail.com.
authors: M A
authors: MA
authors: Islam
authors: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands.
authors: R
authors: R
authors: Bekele
authors: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands.
authors: J H J
authors: JH
authors: Vanden Berg
authors: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands.
authors: Y
authors: Y
authors: Kuswanti
authors: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands.
authors: O
authors: O
authors: Thapa
authors: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands.
authors: S
authors: S
authors: Soltani
authors: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands.
authors: F X R
authors: FX
authors: van Leeuwen
authors: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands.
authors: I M C M
authors: IM
authors: Rietjens
authors: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands.
authors: A J
authors: AJ
authors: Murk
mesh_terms: D000818:Animals; D001940:Breast / Q000166:cytology / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D017930:Genes, Reporter / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D020719:Glucuronides / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007529:Isoflavones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013025:Glycine max / Q000737:chemistry*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D004968:Estrogens, Non-Steroidal; D020719:Glucuronides; D007529:Isoflavones; C004742:daidzein; D019833:Genistein
keywords: Aglycones; Breast cell proliferation; Deconjugation; Estrogenicity; Glucuronides; Isoflavones