title: Phase II metabolism of the soy isoflavones genistein and daidzein in humans, rats and mice: a cross-species and sex comparison.
abstract: 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.
authors.affiliation: Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Haid-und-Neu-Straße 9, 76131, Karlsruhe, Germany.
authors.forename: Sebastian T
authors.initials: ST
authors.lastname: Soukup
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Jussi
authors.initials: J
authors.lastname: Helppi
authors.affiliation: Department of Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University, Cologne, Germany.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Müller
authors.affiliation: Molecular Cell Physiology and Endocrinology, Institute for Zoology, Technische Universität Dresden, Dresden, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Zierau
authors.affiliation: Department of Physiology and Biochemistry of Nutrition, Max Rubner-Institut, Karlsruhe, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Watzl
authors.affiliation: Molecular Cell Physiology and Endocrinology, Institute for Zoology, Technische Universität Dresden, Dresden, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Vollmer
authors.affiliation: Department of Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University, Cologne, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Diel
authors.affiliation: Department of Physiology and Biochemistry of Nutrition, Max Rubner-Institut, Karlsruhe, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Bub
authors.affiliation: Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Haid-und-Neu-Straße 9, 76131, Karlsruhe, Germany. sabine.kulling@mri.bund.de.
authors.forename: Sabine E
authors.initials: SE
authors.lastname: Kulling
mesh_terms: D000328:Adult; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005260:Female; D019833:Genistein / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007529:Isoflavones / Q000097:blood / Q000378:metabolism*; D057230:Limit of Detection; D008297:Male; D013058:Mass Spectrometry; D050217:Metabolic Detoxication, Phase II; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D017698:Postmenopause / Q000097:blood / Q000378:metabolism*; D017208:Rats, Wistar; D012737:Sex Factors; D013025:Glycine max / Q000737:chemistry*; D013045:Species Specificity
chemical_list: D007529:Isoflavones; C004742:daidzein; D019833:Genistein
keywords: Glucuronides; Human; Isoflavones; Mouse; Rat; Sulfates