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 ArticlesThis 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
The development of reliable nonanimal based testing strategies, such as in vitro bioassays, is the holy grail in current human safety testing of chemicals. However, the use of in vitro toxicity data in risk assessment is not straightforward. One of the main issues is that concentration-response curves from in vitro models need to be converted to in vivo dose-response curves. These dose-response curves are needed in toxicological risk assessment to obtain a point of departure to determine safe exposure levels for humans. Recent scientific developments enable this translation of in vitro concentration-response curves to in vivo dose-response curves using physiologically based kinetic (PBK) modeling-based reverse dosimetry. The present review provides an overview of the examples available in the literature on the prediction of in vivo toxicity using PBK modeling-based reverse dosimetry of in vitro toxicity data, showing that proofs-of-principle are available for toxicity end points ranging from developmental toxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity to DNA adduct formation. This review also discusses the promises and pitfalls, and the future perspectives of the approach. Since proofs-of-principle available so far have been provided for the prediction of toxicity in experimental animals, future research should focus on the use of in vitro toxicity data obtained in human models to predict the human situation using human PBK models. This would facilitate human- instead of experimental animal-based approaches in risk assessment.
To quantify interindividual differences in the human intestinal microbial metabolism of (−)-epicatechin (EC), in vitro anaerobic incubations with fecal inocula from 24 healthy donors were conducted. EC-derived colonic microbial metabolites were qualitatively and quantitively analyzed by liquid chromatography triple quadrupole mass spectrometry (LC-TQ-MS) and liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS). Quantitative microbiota characterization was achieved by 16S rRNA analysis. The results obtained show 1-(3′,4′-dihydroxyphenyl)-3-(2″,4″,6″-dihydroxyphenyl)-2-propanol (3,4-diHPP-2-ol) and 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone (3,4-diHPV) to be key intermediate microbial metabolites of EC and also revealed the substantial interindividual differences in both the rate of EC conversion and the time-dependent EC metabolite pattern. Furthermore, substantial differences in microbiota composition among different individuals were detected. Correlations between specific microbial phylotypes and formation of certain metabolites were established. It is concluded that interindividual differences in the intestinal microbial metabolism of EC may contribute to interindividual differences in potential health effects of EC-abundant dietary foods or drinks.
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.
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