Isoflavones, oestrogen like activity

Isoflavones and their similarity to oestrogens., structurally and functionally

Isoflavones are plant chemicals which belong to the family of phyto-oestrogens. There are of interest to nutrition and health due to their potential oestrogenic properties in the body. There is close structural relationship of genistein and daidzein compared with 17ß-oestrodiol. Although oestrogenicity assays have reported low oestrogenic potency for dietary isoflavones (100-1000 times less than I7p-oestradiol;. However when dietary intakes of isoflavones are high their circulating concentrations could exceed endogenous oestradiol concentrations by up to 10000-fold which suggests potential physiological effects.
Isoflavones predominantly occur in plants as the water-soluble ß-glucosides, genistin. daidzin, glycitin which are hydrolysed by intestinal and bacterial ß-glucosidases. Genistein, daidzein and glycitein may be absorbed or further metabolised by gut microflora enzymes to isoflavone metabolites such as equol, dihydrogenistein. dihydrodaidzein, 6′-hydroxy-O-desmethylangolensin and -O-des-methylangolensin before absorption.
There is substantial evidence that oestrogen has beneficial effects on the cardiovascular system by enhancing NO production and thereby maintaining normal endothelial vasodilatory response and integrity of the vascular system. Oestrogen-like compounds such as isoflavones are also suggested to protect the endothelium and therefore be protective against the development of CVD.
Oestrogen-induced NO release occurs by more than one pathway. . Oestrogen can act through the classical oestrogen receptor (ER)-transcriptional pathway, whereby eNOS gene expression is increased and NO production increases over hours or days. The ‘genomic’ effects of oestrogen. However, the acute effects, which are rapid in response and short in duration, may involve ERa-mediated activation of none-transcriptional pathways (non-genomic), or by a direct activation of cell-signalling pathways.
Oestrogen also appears to increase NO availability by modulating reactive oxygen species (ROS) and antioxidant status within the endothelial cell. Oestrogen has been shown to inhibit the production of NADPH oxidase and superoxide, attenuating the potential for superoxide-mediated degradation of NO and formation of peroxynitrites . In addition to its positive effects on NO. oestrogen has been shown to promote the release of other vasodilator agents from endothelium.
There are two known classical oestrogen receptors ERα and ERß both widely distributed throughout the body. Oestrogen, or other oestrogcnic ligands. bind to these nuclear receptors in the cytosol. which allows the receptor to enter the nucleus and bind to response elements on DNA, and modulate gene transcription. ERα and ERß bind to the same oestrogen response elements (therefore affecting transcription of the same genes. However, they are functionally distinct and will not necessarily affect these genes in the same direction or with the same potency Although ERα and ERß are both expressed throughout the vasculature ERB is the receptor that predominates in this tissue, particularly in women. In addition, there are specific functional domains on the two receptor proteins that have a degree of divergence in their homology, which may affect binding of oestrogenic ligands . This is illustrated by the greater binding affinity of isoflavones for ERß compared with ERa .
Since ERa and ERß have different tissue distributions and binding affinities, it seems probable that the protective effects of oestrogen, or indeed oestrogen-like compounds, on the endothelium would vary with receptor type.
ERa appears to be the most important receptor for the protective effects of oestrogen in the endothelium.
Since isoflavones have a greater binding affinity for ERp compared with ERa then it might be expected that any protective effect of isoflavones against vascular injury would be weak compared with that of oestrogen, unless the isoflavone- ERß conformation induced a greater affinity for the oestrogen response element than the oestrogen- ERß conformation. Isoflavones bind more effectively to ERß compared with ERa, but they are also 1000 times more potent at generating transcriptional activity via ERß compared with ERa, due to selective recruitment of co-regulators to ERp. In addition, isoflavones are more effective at triggering transcriptional repression rather than activation, suggesting that isoflavones may repress transcription of some genes that are normally activated by ERa.

Hall WL et al 2005, Nutrition Research Reviews, 18, 130-144

Martin Eastwood
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