Scope: This study compares conversion of three major soy isoflavone glucosides and their aglycones in a series of in vitro intestinal models.
Methods and results:In an in vitro human digestion model isoflavone glucosides were not deconjugated, whereas studies in a Caco-2 transwell model confirmed that deconjugation is essential to facilitate transport across the intestinal barrier. Deconjugation was shown upon incubation of the isoflavone glucosides with rat as well as human intestinal S9. In incubations with rat intestinal S9 lactase phlorizin hydrolase, glucocerebrosidase, and cytosolic broadspecific -glucosidase all contribute significantly to deconjugation, whereas in incubations with human intestinal S9 deconjugation appeared to occur mainly through the activity of broad-specific -glucosidase. Species differences in glucuronidation and sulfation were limited and generally within an order of magnitude with 7-O-glucuronides being the major metabolites for all three isoflavone aglycones and the glucuronidation during first pass metabolism being more efficient in rats than in humans. Comparison of the catalytic efficiencies reveals that deconjugation is less efficient than conjugation confirming that aglycones are unlikely to enter the systemic circulation. Conclusion: Altogether, the data point at possible differences in the characteristics for intestinal conversion of the major soy isoflavones between rat and human, especially with respect to their deconjugation.
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.
The health effects of soy supplementation in (post)menopausal women are still a controversial issue. The aim of the present study was to establish the effect of the soy isoflavones (SIF) present in a commercially available supplement on ovariectomized rats and to investigate whether these rats would provide an adequate model to predict effects of SIF in (post)menopausal women. Two dose levels (i.e. 2 and 20 mg/kg b.w.) were used to characterize plasma bioavailability, urinary and fecal concentrations of SIF and changes in gene expression in peripheral blood mononuclear cells (PBMC). Animals were dosed at 0 and 48 h and sacrificed 4 h after the last dose. A clear dose dependent increase of SIF concentrations in plasma, urine and feces was observed, together with a strong correlation in changes in gene expression between the two dose groups. All estrogen responsive genes and related biological pathways (BPs) that were affected by the SIF treatment were regulated in both dose groups in the same direction and indicate beneficial effects. However, in general no correlation was found between the changes in gene expression in rat PBMC with those in PBMC of (post)menopausal women exposed to a comparable dose of the same supplement. The outcome of this short-term study in rats indicates that the rat might not be a suitable model to predict effects of SIF in humans. Although the relative exposure period in this rat study is comparable with that of the human study, longer repetitive administration of rats to SIF may be required to draw a final conclusion on the suitability of the rat a model to predict effects of SIF in humans.
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