Boonpawa Rungnapa, Spenkelink Albertus, Punt Ans, Rietjens Ivonne M C M
Division of Toxicology, Wageningen University, Wageningen, The Netherlands.
Br J Pharmacol. 2017 Aug;174(16):2739-2757. doi: 10.1111/bph.13900. Epub 2017 Jul 11.
The in vivo oestrogenicity of genistein and its glycoside genistin is still under debate. The present study aimed to develop a physiologically based kinetic (PBK) model that provides insight in dose-dependent plasma concentrations of genistein aglycone and its metabolites and enables prediction of in vivo oestrogenic effective dose levels of genistein and genistin in humans.
A PBK model for genistein and genistin in humans was developed based on in vitro metabolic parameters. The model obtained was used to translate in vitro oestrogenic concentration-response curves of genistein to in vivo oestrogenic dose-response curves for intake of genistein and genistin.
The model predicted that genistein-7-O-glucuronide was the major circulating metabolite and that levels of the free aglycone were generally low [0.5-17% of total plasma genistein at oral doses from 0.01 to 50 mg (kg·bw) ]. The predicted in vivo benchmark dose for 5% response values for oestrogenicity varied between 0.06 and 4.39 mg kg genistein. For genistin, these values were 1.3-fold higher. These values are in line with reported human data and show that oestrogenic responses can be expected at an Asian dietary and a supplementary intake, while intake resulting from a Western diet may not be effective.
The present study shows how plasma concentrations of genistein and its metabolites and oestrogenic dose levels of genistein in humans can be predicted by combining in vitro oestrogenicity with PBK model-based reverse dosimetry, eliminating the need for human intervention studies.
染料木黄酮及其糖苷染料木苷在体内的雌激素活性仍存在争议。本研究旨在建立一个基于生理的动力学（PBK）模型，以深入了解染料木黄酮苷元及其代谢产物的剂量依赖性血浆浓度，并能够预测人体中染料木黄酮和染料木苷的体内雌激素有效剂量水平。
基于体外代谢参数建立了人体中染料木黄酮和染料木苷的PBK模型。所获得的模型用于将染料木黄酮的体外雌激素浓度-反应曲线转化为染料木黄酮和染料木苷摄入的体内雌激素剂量-反应曲线。
该模型预测染料木黄酮-7-O-葡萄糖醛酸苷是主要的循环代谢产物，游离苷元的水平通常较低[口服剂量为0.01至50mg/（kg·bw）时，占血浆总染料木黄酮的0.5-17%]。雌激素活性5%反应值的预测体内基准剂量在0.06至4.39mg/kg染料木黄酮之间变化。对于染料木苷，这些值高1.3倍。这些值与报道的人体数据一致，表明在亚洲饮食和补充摄入时可能会出现雌激素反应，而西方饮食引起的摄入可能无效。
本研究表明，通过将体外雌激素活性与基于PBK模型的反向剂量测定相结合，可以预测人体中染料木黄酮及其代谢产物的血浆浓度以及染料木黄酮的雌激素剂量水平，从而无需进行人体干预研究。
