Soy isoflavones (IF) are in the focus of biomedical research since more than two decades. To assess their bioactivity, IF are investigated in rats and mice as a model. As the biological activity of IF is affected by their biotransformation, our aim was to comprehensively compare the conjugative and microbial metabolism of daidzein and genistein in adult humans, rats and mice of both sexes. One identical soy extract and a validated LC–MS method were used for all studies. We detected considerable differences between the three species. In rats and mice, sex-specific differences were observed in addition. The major plasma phase II metabolites in humans were the 7-sulfo-4′-glucuronides (39–49 %) and, in case of genistein, also the diglucuronide (34 %), whereas in mice monosulfates (33–41 %) and monoglucuronides (30–40 %) predominated. In male rats the disulfates (23–62 %) and 7-sulfo-4′-glucuronides (19–54 %) were predominant, while in female rats the 7-glucuronides (81–93 %) exhibited highest concentrations. The portion of aglycones was low in humans (0.5–1.3 %) and rats (0.5–3.1 %) but comparatively high in mice (3.1–26.0 %), especially in the case of daidzein. Furthermore, substantial differences were observed between daidzein and genistein metabolism. In contrast to humans, all rats and mice were equol producer, independent of their sex. In conclusion, there are marked differences between humans, rats and mice in the profile of major metabolites following IF phase II metabolism. These differences may contribute to resolve inconsistencies in results concerning the bioactivity of IF and should be considered when applying findings of animal studies to humans, e.g., for risk assessment.
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This work was funded by the German Research Foundation (DFG), grants KU 1079/9-1, DI 716/12-2 and VO 410/12-1. The project is part of the collaborative research project entitled IsoCross “Isoflavones: Cross-species comparison on metabolism, estrogen sensitivity, epigenetics, and carcinogenesis”.
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the State Medical Chamber Baden-Württemberg, Stuttgart, Germany, and the ethics commission of the German Sport University Cologne, Cologne, Germany as well as with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All guidelines of the Institutional Animal Care and Use Committee regulated by the German federal law for animal welfare were followed.
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Soukup, S.T., Helppi, J., Müller, D.R. et al. Phase II metabolism of the soy isoflavones genistein and daidzein in humans, rats and mice: a cross-species and sex comparison. Arch Toxicol 90, 1335–1347 (2016). https://doi.org/10.1007/s00204-016-1663-5