Deconjugation of soy isoflavone glucuronides needed for estrogenic activity

M.A. Islam, R. Bekele, J.H.J. van den Berg, Y. Kuswanti, O. Thapa, S. Soltani, F.X.R. Leeuwen, I.M.C.M. Rietjens, A.J. Murk

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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-ERa, U2OS-ERß reporter gene cells and proliferation was tested in T47D-ERß cells mimicking the ERa/ERß 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.
Original languageEnglish
Pages (from-to)706-715
JournalToxicology in Vitro
Volume29
Issue number4
DOIs
Publication statusPublished - 2015

Fingerprint

Isoflavones
Glucuronides
Genistein
Breast
Tissue
Metabolites
Bioactivity
Reporter Genes
Rats
Assays
Animals
Blood
Genes
Cells
Cell Proliferation
Breast Neoplasms

Keywords

  • beta-messenger-rna
  • in-vitro
  • er-beta
  • receptor-beta
  • cell-proliferation
  • human plasma
  • cancer
  • expression
  • alpha
  • genistein

Cite this

Islam, M.A. ; Bekele, R. ; van den Berg, J.H.J. ; Kuswanti, Y. ; Thapa, O. ; Soltani, S. ; Leeuwen, F.X.R. ; Rietjens, I.M.C.M. ; Murk, A.J. / Deconjugation of soy isoflavone glucuronides needed for estrogenic activity. In: Toxicology in Vitro. 2015 ; Vol. 29, No. 4. pp. 706-715.
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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-ERa, U2OS-ER{\ss} reporter gene cells and proliferation was tested in T47D-ER{\ss} cells mimicking the ERa/ER{\ss} 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.",
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author = "M.A. Islam and R. Bekele and {van den Berg}, J.H.J. and Y. Kuswanti and O. Thapa and S. Soltani and F.X.R. Leeuwen and I.M.C.M. Rietjens and A.J. Murk",
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Deconjugation of soy isoflavone glucuronides needed for estrogenic activity. / Islam, M.A.; Bekele, R.; van den Berg, J.H.J.; Kuswanti, Y.; Thapa, O.; Soltani, S.; Leeuwen, F.X.R.; Rietjens, I.M.C.M.; Murk, A.J.

In: Toxicology in Vitro, Vol. 29, No. 4, 2015, p. 706-715.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Deconjugation of soy isoflavone glucuronides needed for estrogenic activity

AU - Islam, M.A.

AU - Bekele, R.

AU - van den Berg, J.H.J.

AU - Kuswanti, Y.

AU - Thapa, O.

AU - Soltani, S.

AU - Leeuwen, F.X.R.

AU - Rietjens, I.M.C.M.

AU - Murk, A.J.

PY - 2015

Y1 - 2015

N2 - 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-ERa, U2OS-ERß reporter gene cells and proliferation was tested in T47D-ERß cells mimicking the ERa/ERß 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.

AB - 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-ERa, U2OS-ERß reporter gene cells and proliferation was tested in T47D-ERß cells mimicking the ERa/ERß 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.

KW - beta-messenger-rna

KW - in-vitro

KW - er-beta

KW - receptor-beta

KW - cell-proliferation

KW - human plasma

KW - cancer

KW - expression

KW - alpha

KW - genistein

U2 - 10.1016/j.tiv.2015.01.013

DO - 10.1016/j.tiv.2015.01.013

M3 - Article

VL - 29

SP - 706

EP - 715

JO - Toxicology in Vitro

JF - Toxicology in Vitro

SN - 0887-2333

IS - 4

ER -