Isoflavones: estrogenic activity, biological effect and bioavailability
01 Mar 2013-European Journal of Drug Metabolism and Pharmacokinetics (Springer-Verlag)-Vol. 38, Iss: 1, pp 15-25
TL;DR: The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects and Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability.
Abstract: Isoflavones are phytoestrogens with potent estrogenic activity; genistein, daidzein and glycitein are the most active isoflavones found in soy beans. Phytoestrogens have similarity in structure with the human female hormone 17-β-estradiol, which can bind to both alpha and beta estrogen receptors, and mimic the action of estrogens on target organs, thereby exerting many health benefits when used in some hormone-dependent diseases. Numerous clinical studies claim benefits of genistein and daidzein in chemoprevention of breast and prostate cancer, cardiovascular disease and osteoporosis as well as in relieving postmenopausal symptoms. The ability of isoflavones to prevent cancer and other chronic diseases largely depends on pharmacokinetic properties of these compounds, in particular absorption and distribution to the target tissue. The chemical form in which isoflavones occur is important because it influences their bioavailability and, therefore, their biological activity. Glucose-conjugated isoflavones are highly polar, water-soluble compounds. They are hardly absorbed by the intestinal epithelium and have weaker biological activities than the corresponding aglycone. Different microbial families of colon can transform glycosylated isoflavones into aglycones. Clinical studies show important differences between the aglycone and conjugated forms of genistein and daidzein. The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects. Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability. Complexation with cyclodextrin also represent a valid method to improve the physicochemical characteristics of these substances in order to be absorbed and distributed to target tissues. We review and discuss pharmacokinetic issues that critically influence the biological activity of isoflavones.
Citations
More filters
TL;DR: Plytoestrogens and phytoestrogen-containing diet can be useful for the prevention and treatment of menopausal symptoms, skin aging, osteoporosis, cancer, cardiovascular, neurodegenerative, immune and metabolic diseases.
268 citations
Cites background from "Isoflavones: estrogenic activity, b..."
...Following absorption, isoflavones are then reconjugated mainly to glucuronic and sulfuric acids (Cassidy, 2003; Chiang and Pan, 2013; Vitale et al., 2013)....
[...]
TL;DR: Overall, progress has been made in understanding the functional and bioactive components of soy, however, more studies are required to further identify their target organs, and elucidate their biological mechanisms of action in order to be potentially used as functional foods or even therapeutics for the prevention or treatment of chronic diseases.
Abstract: Soy consumption has been associated with many potential health benefits in reducing chronic diseases such as obesity, cardiovascular disease, insulin-resistance/type II diabetes, certain type of cancers, and immune disorders. These physiological functions have been attributed to soy proteins either as intact soy protein or more commonly as functional or bioactive peptides derived from soybean processing. These findings have led to the approval of a health claim in the USA regarding the ability of soy proteins in reducing the risk for coronary heart disease and the acceptance of a health claim in Canada that soy protein can help lower cholesterol levels. Using different approaches, many soy bioactive peptides that have a variety of physiological functions such as hypolipidemic, anti-hypertensive, and anti-cancer properties, and anti-inflammatory, antioxidant, and immunomodulatory effects have been identified. Some soy peptides like lunasin and soymorphins possess more than one of these properties and play a role in the prevention of multiple chronic diseases. Overall, progress has been made in understanding the functional and bioactive components of soy. However, more studies are required to further identify their target organs, and elucidate their biological mechanisms of action in order to be potentially used as functional foods or even therapeutics for the prevention or treatment of chronic diseases.
261 citations
TL;DR: The anti-inflammatory effects of isoflavones are summarized, the underlying mechanisms are unraveled, the potential health risks are presented, and the potential risks and benefits are presented.
Abstract: Inflammation, a biological response of body tissues to harmful stimuli, is also known to be involved in a host of diseases, such as obesity, atherosclerosis, rheumatoid arthritis, and even cancer. Isoflavones are a class of flavonoids that exhibit antioxidant, anticancer, antimicrobial, and anti-inflammatory properties. Increasing evidence has highlighted the potential for isoflavones to prevent the chronic diseases in which inflammation plays a key role, though the underlying mechanisms remain unclear. Recently, some studies have raised concerns about isoflavones induced negative effects like carcinogenesis, thymic involution, and immunosuppression. Therefore, this review aims to summarize the anti-inflammatory effects of isoflavones, unravel the underlying mechanisms, and present the potential health risks.
200 citations
Cites background from "Isoflavones: estrogenic activity, b..."
...to exert pseudohormonal activity by binding to estrogen receptors (ER) in mammals [25,26], and also possess antioxidant, anticancer, antimicrobial, and anti-inflammatory activities just like other flavonoids [27–30]....
[...]
...pseudohormonal activity by binding to estrogen receptors (ER) in mammals [25,26], and also possess antioxidant, anticancer, antimicrobial, and anti‐inflammatory activities just like other flavonoids [27–30]....
[...]
TL;DR: The complexity of these emerging pathways and corresponding biological responses highlights the rapid advances in nutritional science and the continued need to generate robust empirical evidence on the mechanistic and clinical effects of specific foods.
Abstract: A growing body of nutritional science highlights the complex mechanisms and pleiotropic pathways of cardiometabolic effects of different foods. Among these, some of the most exciting advances are o...
194 citations
TL;DR: Current knowledge on the microorganisms involved in, the genetic background to, and the biochemical pathways of, equol biosynthesis are summarized and the results of recent clinical trials and meta-analyses on the effects of equol on different areas of human health are outlined.
Abstract: Epidemiological data suggest that regular intake of isoflavones from soy reduces the incidence of estrogen-dependent and aging-associated disorders, such as menopause symptoms in women, osteoporosis, cardiovascular diseases and cancer. Equol, produced from daidzein, is the isoflavone-derived metabolite with the greatest estrogenic and antioxidant activity. Consequently, equol has been endorsed as having many beneficial effects on human health. The conversion of daidzein into equol takes place in the intestine via the action of reductase enzymes belonging to incompletely characterized members of the gut microbiota. While all animal species analyzed so far produce equol, only between one third and one half of human subjects (depending on the community) are able to do so, ostensibly those that harbor equol-producing microbes. Conceivably, these subjects might be the only ones who can fully benefit from soy or isoflavone consumption. This review summarizes current knowledge on the microorganisms involved in, the genetic background to, and the biochemical pathways of, equol biosynthesis. It also outlines the results of recent clinical trials and meta-analyses on the effects of equol on different areas of human health and discusses briefly its presumptive mode of action.
189 citations
Cites background from "Isoflavones: estrogenic activity, b..."
...Soy isoflavones are phytoestrogens resembling 17-β-estradiol; although less active than the hormone, they show estrogen-like activity [5]....
[...]
References
More filters
TL;DR: This issue of Pharmacological Reviews includes a new venture in the collaboration between the International Union of Pharmacology (IUPHAR) and the American Society for Pharmacology and Experimental Therapeutics (ASPET), in that a new classification of voltage-gated ion channels is outlined.
Abstract: This issue of Pharmacological Reviews includes a new venture in the collaboration between the International Union of Pharmacology (IUPHAR) and the American Society for Pharmacology and Experimental Therapeutics (ASPET), in that a new classification of voltage-gated ion channels is outlined in this
7,389 citations
TL;DR: It is concluded that clone 29 cDNA encodes a novel rat ER, which is suggested be named rat ERbeta to distinguish it from the previously cloned ER (ERalpha) from rat uterus.
Abstract: We have cloned a novel member of the nuclear receptor superfamily. The cDNA of clone 29 was isolated from a rat prostate cDNA library and it encodes a protein of 485 amino acid residues with a calculated molecular weight of 54.2 kDa. Clone 29 protein is unique in that it is highly homologous to the rat estrogen receptor (ER) protein, particularly in the DNA-binding domain (95%) and in the C-terminal ligand-binding domain (55%). Expression of clone 29 in rat tissues was investigated by in situ hybridization and prominent expression was found in prostate and ovary. In the prostate clone 29 is expressed in the epithelial cells of the secretory alveoli, whereas in the ovary the granuloma cells in primary, secondary, and mature follicles showed expression of clone 29. Saturation ligand-binding analysis of in vitro synthesized clone 29 protein revealed a single binding component for 17beta-estradiol (E2) with high affinity (Kd= 0.6 nM). In ligand-competition experiments the binding affinity decreased in the order E2 > diethylstilbestrol > estriol > estrone > 5alpha-androstane-3beta,17beta-diol >> testosterone = progesterone = corticosterone = 5alpha-androstane-3alpha,17beta-diol. In cotransfection experiments of Chinese hamster ovary cells with a clone 29 expression vector and an estrogen-regulated reporter gene, maximal stimulation (about 3-fold) of reporter gene activity was found during incubation with 10 nM of E2. Neither progesterone, testosterone, dexamethasone, thyroid hormone, all-trans-retinoic acid, nor 5alpha-androstane-3alpha,I7beta-diol could stimulate reporter gene activity, whereas estrone and 5alpha-androstane-3beta,17beta-diol did. We conclude that clone 29 cDNA encodes a novel rat ER, which we suggest be named rat ERbeta to distinguish it from the previously cloned ER (ERalpha) from rat uterus.
4,782 citations
"Isoflavones: estrogenic activity, b..." refers background in this paper
...Interestingly, ERb is found in brain, bone, bladder and vascular epithelia (Kuiper et al. 1996, 1997; Hillier et al. 1998), tissues that are responsive to classical hormone replacement therapy (HRT)....
[...]
...Estrogens exert their genomic effects mainly via two nuclear receptors, ERa and ERb (Dahlman-Wright et al. 2006; Kuiper et al. 1996; Paech et al. 1997), that play different roles in gene regulation....
[...]
TL;DR: The messenger RNA expression of both ER subtypes in rat tissues by RT-PCR is investigated and the ligand binding specificity of the ER sub types is compared, revealing a single binding component for 16β-estradiol with high affinity.
Abstract: The rat estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study we investigated the messenger RNA expression of both ER subtypes in rat tissues by RT-PCR and compared the ligand binding specificity of the ER subtypes. Saturation ligand binding analysis of in vitro synthesized human ER alpha and rat ER beta protein revealed a single binding component for 16 alpha-iodo-17 beta-estradiol with high affinity [dissociation constant (Kd) = 0.1 nM for ER alpha protein and 0.4 nM for ER beta protein]. Most estrogenic substances or estrogenic antagonists compete with 16 alpha-[125I]iodo-17 beta-estradiol for binding to both ER subtypes in a very similar preference and degree; that is, diethylstilbestrol > hexestrol > dienestrol > 4-OH-tamoxifen > 17 beta-estradiol > coumestrol, ICI-164384 > estrone, 17 alpha-estradiol > nafoxidine, moxestrol > clomifene > estriol, 4-OH-estradiol > tamoxifen, 2-OH-estradiol, 5-androstene-3 beta, 17 beta-diol, genistein for the ER alpha protein and dienestrol > 4-OH-tamoxifen > diethylstilbestrol > hexestrol > coumestrol, ICI-164384 > 17 beta-estradiol > estrone, genistein > estriol > nafoxidine, 5-androstene-3 beta, 17 beta-diol > 17 alpha-estradiol, clomifene, 2-OH-estradiol > 4-OH-estradiol, tamoxifen, moxestrol for the ER beta protein. The rat tissue distribution and/or the relative level of ER alpha and ER beta expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ER alpha and prostate, ovary, lung, bladder, brain, uterus, and testis for ER beta. The described differences between the ER subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues.
4,367 citations
TL;DR: Genistein inhibited the EGF-stimulated increase in phosphotyrosine level in A431 cells and scarcely inhibited the enzyme activities of serine- and threonine-specific protein kinases such as cAMP-dependent protein kinase, phosphorylase kinases, and the Ca2+/phospholipid-dependent enzymeprotein kinase C.
3,761 citations
"Isoflavones: estrogenic activity, b..." refers background in this paper
...Moreover, genistein is a potent inhibitor of tyrosine kinase (Akiyama et al. 1987), which may affect Syk kinase and thrombin generation (van der Meijden et al....
[...]
...Moreover, genistein is a potent inhibitor of tyrosine kinase (Akiyama et al. 1987), which may affect Syk kinase and thrombin generation (van der Meijden et al. 2012)....
[...]
...1997), inhibit protein-tyrosine kinase mediated signal transduction (Akiyama et al. 1987), inhibit DNA topoisomerase (ATP-hydrolyzing) (Yamashita et al....
[...]
...…et al. 1994), have antioxidant activities (Wei et al. 1996; Kapiotis et al. 1997), inhibit protein-tyrosine kinase mediated signal transduction (Akiyama et al. 1987), inhibit DNA topoisomerase (ATP-hydrolyzing) (Yamashita et al. 1990; Constantinou et al. 1995), inhibit transforming growth…...
[...]
TL;DR: In this article, a cell comprising an estrogen receptor beta (ER beta ), AP1 proteins, and a construct comprising a promoter comprising an AP1 site which regulates expression of a first reporter gene is contacted with the test compound and changes in expression levels of the reporter gene are detected indicating whether the test compounds activate transcription, inactivate transcription or have no effect at the AP1 sites.
Abstract: This invention provides methods of screening test compounds for the ability to activate or inhibit estrogen receptor beta (ER beta ) mediated gene activation at an AP1 site. In particular, the methods involve providing a cell comprising an estrogen receptor beta (ER beta ), AP1 proteins, and a construct comprising a promoter comprising an AP1 site which regulates expression of a first reporter gene. The cell is contacted with the test compound and changes in expression levels of the reporter gene are detected indicating whether the test compounds activate transcription, inactivate transcription or have no effect at the AP1 site.
2,175 citations