Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ERα and ERβ. Transgenic mice in which each of the receptors or both the receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This decade also saw the description of a male patient who had no functional ERα and whose continued bone growth clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally, crystal structures of the estrogen r...

Mechanisms of Estrogen Action

Phytochemicals, as plant components with discrete bio-activities towards animal biochemistry and metabolism are being widely examined for their ability to provide health benefits. It is important to establish the scientific rationale to defend their use in foods, as potential nutritionally active ingredients. Phytochemicals could provide health benefits as: (1) substrates for biochemical reactions; (2) cofactors of enzymatic reactions; (3) inhibitors of enzymatic reactions; (4) absorbents/sequestrants that bind to and eliminate undesirable constituents in the intestine; (5) ligands that agonize or antagonize cell surface or intracellular receptors; (6) scavengers of reactive or toxic chemicals; (7) compounds that enhance the absorption and or stability of essential nutrients; (8) selective growth factors for beneficial gastrointestinal bacteria; (9) fermentation substrates for beneficial oral, gastric or intestinal bacteria; and (10) selective inhibitors of deleterious intestinal bacteria. Such phytochemicals include terpenoids, phenolics, alkaloids and fiber. Research supporting beneficial roles for phytochemicals against cancers, coronary heart disease, diabetes, high blood pressure, inflammation, microbial, viral and parasitic infections, psychotic diseases, spasmodic conditions, ulcers, etc is based on chemical mechanisms using in vitro and cell culture systems, various disease states in animals and epidemiology of humans. However, it must be emphasized that a distinction needs to be drawn between the types of information that can be obtained from studies in vitro, in animals and in humans. Mechanisms of action must certainly be established in vitro; however, the efficacy of these same ingredients with their mechanisms of action, must also be demonstrated in vivo. The rapid growth in the use of phytochemicals in nutraceutical and functional foods requires that the food and pharmaceutical industries face new challenges: in addressing worldwide public concern over the efficacy and safety of supplements and foods claimed to be health-promoting; in government regulations related to safety, labeling and health claims for products that contain phytochemicals; in the manufacturing of foods with different qualities and stabilities; and in marketing issues, particularly as they relate to consumers' recognizing added value.

© 2000 Society of Chemical Industry

Phytochemicals: nutraceuticals and human health.

Through an effort to develop novel ligands that have subtype selectivity for the estrogen receptors alpha (ERalpha) and beta (ERbeta), we have found that 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) acts as an agonist on both ER subtypes, but has a 70-fold higher relative binding affinity and 170-fold higher relative potency in transcription assays with ERbeta than with ERalpha. To investigate the ERbeta affinity- and potency-selective character of this DPN further, we prepared a series of DPN analogues in which both the ligand core and the aromatic rings were modified by the repositioning of phenolic hydroxy groups and by the addition of alkyl substituents and nitrile groups. We also prepared other series of DPN analogues in which the nitrile functionality was replaced with acetylene groups or polar functions, to mimic the linear geometry or polarity of the nitrile, respectively. To varying degrees, all of the analogues show preferential binding affinity for ERbeta (i.e., they are ERbeta affinity-selective), and many, but not all of them, are also more potent in activating transcription through ERbeta than through ERalpha (i.e., they are ERbeta potency-selective). meso-2,3-Bis(4-hydroxyphenyl)succinonitrile and dl-2,3-bis(4-hydroxyphenyl)succinonitrile are among the highest ERbeta affinity-selective ligands, and they have an ERbeta potency selectivity that is equivalent to that of DPN. The acetylene analogues have higher binding affinities but somewhat lower selectivities than their nitrile counterparts. The polar analogues have lower affinities, and only the fluorinated polar analogues have substantial affinity selectivities. This study suggests that, in this series of ligands, the nitrile functionality is critical to ERbeta selectivity because it provides the optimal combination of linear geometry and polarity. Furthermore, the addition of a second nitrile group beta to the nitrile in DPN or the addition of a methyl substitutent at an ortho position on the beta-aromatic ring increases the affinity and selectivity of these compounds for ERbeta. These ERbeta-selective compounds may prove to be valuable tools in understanding the differences in structure and biological function of ERalpha and ERbeta.

Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues.

The pros and cons of phytoestrogens

Members of the nuclear-receptor superfamily mediate crucial physiological functions by regulating the synthesis of their target genes. Nuclear receptors are usually activated by ligand binding. Cytochrome P450 (CYP) isoforms often catalyse both formation and degradation of these ligands. CYPs also metabolize many exogenous compounds, some of which may act as activators of nuclear receptors and disruptors of endocrine and cellular homoeostasis. This review summarizes recent findings that indicate that major classes of CYP genes are selectively regulated by certain ligand-activated nuclear receptors, thus creating tightly controlled networks.

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Regulation of cytochrome P450 (CYP) genes by nuclear receptors

Estrogen-based drug therapy in cardiovascular diseases has been difficult because it has not been possible to separate the wanted vasculoprotective effect from the unwanted effects of the hormone to the reproductive system. Here, we demonstrate that, after endothelial denudation of rat carotid artery, the mRNA of the classical estrogen receptor (ERalpha) is constitutively expressed at a low level whereas the expression of the novel ERbeta mRNA increases >40-fold. Under in situ hybridization and immunohistochemistry, ERbeta mRNA and protein colocalize with the smooth muscle cells in the media and neointima. Treatment of ovariectomized female rats with the isoflavone phytoestrogen genistein, which shows 20-fold higher binding affinity to ERbeta than to ERalpha, or with 17beta-estradiol, which does not differentiate between the two receptors, provides similar dose-dependent vasculoprotective effect in rat carotid injury model. In addition in concentrations <10 microM, both ligands are equally inhibitory to the replication and migration of smooth muscle cells in vitro. However, only treatment with 17beta-estradiol, but not with genistein, is accompanied with a dose-dependent uterotrophic effect. The results suggest that preferential targeting to ERbeta will provide vasculoprotective estrogen analogs devoid of effects to the reproductive system.

https://www.pnas.org/content/pnas/96/12/7077.full.pdf

Hanna Savolainen

Papers

Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors α and β