TY - JOUR
T1 - Use of Physiologically Based Kinetic Modeling to Predict Rat Gut Microbial Metabolism of the Isoflavone Daidzein to S-Equol and Its Consequences for ERα Activation
AU - Wang, Qianrui
AU - Spenkelink, Bert
AU - Boonpawa, Rungnapa
AU - Rietjens, Ivonne M.C.M.
AU - Beekmann, Karsten
PY - 2020/3
Y1 - 2020/3
N2 - Scope: To predict gut microbial metabolism of xenobiotics and the resulting plasma concentrations of metabolites formed, an in vitro–in silico-based testing strategy is developed using the isoflavone daidzein and its gut microbial metabolite S-equol as model compounds. Methods and results: Anaerobic rat fecal incubations are optimized and performed to derive the apparent maximum velocities (Vmax) and Michaelis–Menten constants (Km) for gut microbial conversion of daidzein to dihydrodaidzein, S-equol, and O-desmethylangolensin, which are input as parameters for a physiologically based kinetic (PBK) model. The inclusion of gut microbiota in the PBK model allows prediction of S-equol concentrations and slightly reduced predicted maximal daidzein concentrations from 2.19 to 2.16 µm. The resulting predicted concentrations of daidzein and S-equol are comparable to in vivo concentrations reported. Conclusion: The optimized in vitro approach to quantify kinetics for gut microbial conversions, and the newly developed PBK model for rats that includes gut microbial metabolism, provide a unique tool to predict the in vivo consequences of daidzein microbial metabolism for systemic exposure of the host to daidzein and its metabolite S-equol. The predictions reveal a dominant role for daidzein in ERα-mediated estrogenicity despite the higher estrogenic potency of its microbial metabolite S-equol.
AB - Scope: To predict gut microbial metabolism of xenobiotics and the resulting plasma concentrations of metabolites formed, an in vitro–in silico-based testing strategy is developed using the isoflavone daidzein and its gut microbial metabolite S-equol as model compounds. Methods and results: Anaerobic rat fecal incubations are optimized and performed to derive the apparent maximum velocities (Vmax) and Michaelis–Menten constants (Km) for gut microbial conversion of daidzein to dihydrodaidzein, S-equol, and O-desmethylangolensin, which are input as parameters for a physiologically based kinetic (PBK) model. The inclusion of gut microbiota in the PBK model allows prediction of S-equol concentrations and slightly reduced predicted maximal daidzein concentrations from 2.19 to 2.16 µm. The resulting predicted concentrations of daidzein and S-equol are comparable to in vivo concentrations reported. Conclusion: The optimized in vitro approach to quantify kinetics for gut microbial conversions, and the newly developed PBK model for rats that includes gut microbial metabolism, provide a unique tool to predict the in vivo consequences of daidzein microbial metabolism for systemic exposure of the host to daidzein and its metabolite S-equol. The predictions reveal a dominant role for daidzein in ERα-mediated estrogenicity despite the higher estrogenic potency of its microbial metabolite S-equol.
KW - daidzein
KW - gut microbiota
KW - in vitro–in silico strategy
KW - physiologically based kinetic modeling
KW - S-equol
U2 - 10.1002/mnfr.201900912
DO - 10.1002/mnfr.201900912
M3 - Article
C2 - 32027771
AN - SCOPUS:85082094050
SN - 1613-4125
VL - 64
JO - Molecular Nutrition and Food Research
JF - Molecular Nutrition and Food Research
IS - 6
M1 - 1900912
ER -