Phytoestrogens are plant‐derived dietary compounds with structural similarity to 17‐β‐oestradiol (E2), the primary female sex hormone. This structural similarity to E2 enables phytoestrogens to cause (anti)oestrogenic effects by binding to the oestrogen receptors. The aim of the present review is to present a state‐of‐the‐art overview of the potential health effects of dietary phytoestrogens. Various beneficial health effects have been ascribed to phytoestrogens, such as a lowered risk of menopausal symptoms like hot flushes and osteoporosis, lowered risks of cardiovascular disease, obesity, metabolic syndrome and type 2 diabetes, brain function disorders, breast cancer, prostate cancer, bowel cancer and other cancers. In contrast to these beneficial health claims, the (anti)oestrogenic properties of phytoestrogens have also raised concerns since they might act as endocrine disruptors, indicating a potential to cause adverse health effects. The literature overview presented in this paper illustrates that several potential health benefits of phytoestrogens have been reported but that, given the data on potential adverse health effects, the current evidence on these beneficial health effects is not so obvious that they clearly outweigh the possible health risks. Furthermore, the data currently available are not sufficient to support a more refined (semi) quantitative risk–benefit analysis. This implies that a definite conclusion on possible beneficial health effects of phytoestrogens cannot be made.Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc

Diets rich in flavonoids are associated with various positive health effects. Most in vitro research conducted to elucidate the modes of action of flavonoids uses flavonoid aglycones, but not their circulating conjugated metabolites. Conjugation alters the physico-chemical properties of flavonoids and it is widely assumed that this can affect their biological activity. This article gives a state-of-the-art overview of scientific literature reporting on the effect of metabolic conjugation on the biological activity of flavonoids. The biological activity of flavonoid aglycones is compared to that of their conjugates for a broad range of endpoints. Even though there is only limited literature available, it is shown that contrary to common belief, conjugation does not always decrease the biological activity of flavonoids. There are also endpoints which are unaffected by conjugation, and endpoints on which the conjugates have a higher or inverse activity when compared to the aglycone. The effects of conjugation can differ depending on the type and position of conjugation, the flavonoid concentration, the endpoint studied and the assay system used so that no general rules can be deducted. It is concluded that further studies on the effects of conjugation have to be done on a case-by-case basis, and characterization of the stability and metabolic fate of the flavonoids in the assay system under consideration is needed to avoid false positive or false negative outcomes.

The consumption of dietary flavonoids has been associated with a variety of health benefits, including effects mediated by the activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Flavonoids are extensively metabolized during and after uptake and there is little known on the biological effects of these conjugated metabolites of flavonoids that are found in plasma. To investigate the effect of glucuronidation on the ability of flavonoids to activate PPAR-γ we studied and compared the activity of quercetin, kaempferol and their relevant plasma conjugates quercetin-3-O-glucuronide (Q3G) and kaempferol-3-O-glucuronide (K3G) on different PPAR-γ related endpoints. The flavonoid aglycones increased PPAR-γ mediated gene expression in a stably transfected reporter gene cell line and glucuronidation diminished their effect. To study the intrinsic activity of the test compounds to activate PPAR-γ we used a novel microarray technique to study ligand induced ligand binding domain (LBD) – nuclear receptor coregulator interactions. In this cell-free system we demonstrate that, unlike the known PPAR-γ agonist rosiglitazone, neither the flavonoid aglycones nor the conjugates are agonistic ligands of the receptor. The increases in reporter gene expression in the reporter cells were accompanied by increased PPAR-γ receptor-mRNA expression and quercetin synergistically increased the effect of rosiglitazone in the reporter gene assay. It is concluded that flavonoids affect PPAR-γ mediated gene transcription by a mode of action different from agonist binding. Increases in PPAR-γ receptor mRNA expression and synergistic effects with endogenous PPAR-γ agonists may play a role in this alternative mode of action. Glucuronidation reduced the activity of the flavonoid aglycones.

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 (V_max) and Michaelis–Menten constants (K_m) 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.