Division of Toxicology, Wageningen University and Research, Wageningen, 6708 WE, The Netherlands.
Faculty of Natural Resources and Agro-Industry, Kasetsart University Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon, 47000, Thailand.
Mol Nutr Food Res. 2020 Mar;64(6):e1900912. doi: 10.1002/mnfr.201900912. Epub 2020 Feb 25.
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.
Anaerobic rat fecal incubations are optimized and performed to derive the apparent maximum velocities (V ) and Michaelis-Menten constants (K ) 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.
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.
为了预测外源性物质在肠道微生物中的代谢以及由此形成的代谢物在血浆中的浓度，我们开发了一种基于体外-计算的测试策略，该策略以异黄酮染料木黄酮及其肠道微生物代谢物 S-雌马酚为模型化合物。
优化并进行了厌氧大鼠粪便孵育，以得出肠道微生物将染料木黄酮转化为二氢染料木黄酮、S-雌马酚和 O-去甲安哥拉辛的表观最大速度（V）和米氏常数（K），这些参数被输入到生理相关的动力学（PBK）模型中。在 PBK 模型中包含肠道微生物群，可预测 S-雌马酚的浓度，并略微降低预测的最大染料木黄酮浓度，从 2.19 降至 2.16µm。由此预测的染料木黄酮和 S-雌马酚浓度与体内报道的浓度相当。
优化的体外方法可定量肠道微生物转化的动力学，新开发的包含肠道微生物代谢的大鼠 PBK 模型，为预测染料木黄酮微生物代谢对宿主系统暴露于染料木黄酮及其代谢物 S-雌马酚的体内后果提供了独特的工具。预测结果表明，尽管其微生物代谢物 S-雌马酚的雌激素效力更高，但染料木黄酮在 ERα 介导的雌激素活性中起主导作用。
