1.
Sources and Structure
1.1
Sources
The term soy isoflavones refers to three molecules that are present in food, although most famously contained in soy products; this includes:
- Genistein, and its glycoside Genistin at 30-60% of total soy isoflavones[2]
- Daidzein and its glycoside Daidzin at 40-60% of total soy isoflavones[2]
- Glycitein, and its glycoside Glycitin at around 1-13% of total isoflavones[2]
Of these, genistein and daidzein are seen as the major components of soy due to their relative quantities and equol is also researched a fair bit (despite being a metabolite of daidzein not naturally occurring in soy) due to its potency.
Soy isoflavone is a term used to refer to three isoflavone molecules (genistein, daidzein, and glycitein) as well as their glycosides and metabolites. The content of genistein and daidzein are pretty equivalent in food, with glycitein being much lower
Despite being called 'soy' isoflavones (referring to the Glycine max plant) these above isoflavones can be found in a variety of common food sources including:
Daidzein Genistein Glycitein
- Glycine max (Soybean; main source)[3] at 405-894µg/g (Genistein), 424-1,138µg/g (Daidzein), and 44-145µg/g Glycitein fresh weight[2]
- Black soybean at 579-831µg/g genistein, 452-599µg/g daidzein, and 37-41µg/g glycitein fresh weight[2]
- Green soybean at 335-701µg/g genistein, 630-650µg/g daidzein, and 39-44µg/g glycitein[2]
- Boiled soybean at 354-428µg/g genistein, 270-369µg/g daidzein, and 9-24µg/g glycitein[2]
- Roasted soybean at 892µg/g genistein, 970µg/g daidzein, and 144µg/g glycitein[2] and Kinako (roasted soybean flour) at 830-1,280µg/g genistein, and 1,181-1844µg/g daidzein, 80-100µg/g glycitein fresh weight[2]
- Okara at 48µg/g genistein, 45µg/g daidzein, and 12µg/g glycitein[2]
- Soy milk (1.9-13.9μg/g genistein and genistin)[4]
- Tofu (94.8-137.7μg/g combined genistein and genistin of which 80-112μg/g is genistein[4][4]) with 75-106μg/g daidzein and 24-29μg/g glycitein fresh weight[4]
- Fermented soy bean products (Miso and Natto) at 38.5-229.1μg/g genistein and 71.7-492.8μg/g genistin,[4] with other sources suggesting higher level of genistein (296-440μg/g and 101-319μg/g in natto and miso, respectively), daidzein (323-342μg/g in natto and 108-363μg/g in miso), and glycitein (37-69μg/g in natto and 12-54μg/g in miso)[4]
- Soy sauce at 1-4μg/mL genistein, 5-9μg/mL daidzein, and 1-2.5μg/mL glycitein[4]
- Other legumes (more than 400mg/kg dry weight)[5]
- Indian bread root[5]
- Soy protein isolate (80-107mg per 40g) which can be reduced by alcohol extraction (4.4-6mg per 40g) with an isoflavone breakdown of 53-57% genistein, 20-35% daidzein, and 11-23%[6][7]
When looking at food products, most soy based products seem to have practically comparable levels of isoflavones when looking at fresh weights (Kinako appears to have more due to a lower water content), although roasting and fermentation appear to increase the content of the aglycones (genistein, daidzein, glycitein) relative to the glycosides (genistin, daidzin, glycitin)
And other herbs that are sometimes used for supplemental or medicinal purposes including:
- Hydrocotyle sibthorpioides[8]
- Kudzu root (pueraria lobata)[9] and White Kwao Krua (Pueraria Mirifica) with the latter reaching 8.4-10.2% total estrogenic isoflavones by dry weight[10]
- Psoralea species, including Psoralea corylifolia[9]
- Butea Superba (Genistein and Daidzein)[11]
- Hibiscus Sabdariffa (Daidzein)[12]
- Oxytropis falcate (Genistin and Daidzein)[13]
The soy isoflavones are found in a wide variety of vegetables and legumes
Food sources are typically as Genistin, which is a Genistein molecule bound to a sugar. It is biologically inactive, and during high-temperature heating is reduced to a smaller sized simple glycoside[14] that can be hydrolyzed in the intestine to form the bioavailable genistein aglycone which is then absorbed.[3] The former processing is traditional Eastern Asia processing, and soy foods made from soy flour (from hexane treatment of soybean flakes) standard in North America can either have their isoflavones lost in the hexane extract or decarboxylate their complex glycoside (6′′-O-malonyl-7-O-β-D-glucoside) into another structure (6′′-O-acetyl-7-O-β-D-glucoside) with altered pharmacokinetics.[15] If not broken down into the simple glycoside by heat, genistein cannot be absorbed in the small intestine by the enzyme lactase phlorizin hydrolase.[16]
Fermenting of food sources tends to break the glycoside, and release the free aglcyone (Genistein). Additionally, the free aglycone can be hydroxylated with further fermantation, which increases the anti-oxidative potential of isoflavones.[17][15] Fermented soy sauces contain the compounds 6-hydroxygenistein, 8-hydroxygenistein, and genistein-7-tataric acid. These compounds are not in unfermented soy.[15]
Food products tend to contain the glycosides (isoflavone attached to a sugar) which is readily broken into the free isoflavone in some intestinal bacteria and during the fermentation process
The total intake of isoflavonoids in the japanese diet have been reported to be 27.80 mg per day (daidzein 12.02 mg, glycitein 2.30 mg, and genistein 13.48 mg).[2]
Daily intake of genistein has been suggested to be around 1.5-4.1mg per Japanese person.[4]
Daily intake of genistin has been suggested to be around 6.3–8.3mg per Japanese person.[4]
1.2
Structure
Genistein is an isoflavonoid compound, and is defined by having a hydroxy group on the 4' position of the outermost benzene ring.[18]
2.
Pharmacology
2.2
Metabolism
Daidzein can be metabolized by gut microflora (bacteria) into an estrogenic metabolite called Equol.[23][22] In this process Daidzein is first hydrated to Dihydrodaidzein, which can then either turn into Equol or into O-Desmethylangolensin. This conversion is dependent on gut microflora and varies between individuals[24] which is a reason for reported individual differences in estrogen status among people who consume soy.[25] It has been noted that not all individuals may produce Equol from Daidzein[26][23] and that only 33-50% of humans may possess this bacterial strain.[25][21]
Persons who possess intestinal bacteria to metabolize Daidzein into Equol are classified as 'Equol Producers' and are more likely to experience estrogenic effects from soy.
2.3
Enzymatic Interactions
Many actions on steroid metabolism come from Genistein's interactions with the aromatase enzyme. This is the rate-limiting enzyme that converts androsterone and testosterone to estrone and estradiol, respectively.[27][28] Many isoflavones and flavones can interact with aromatase, in which the binding site for the androgen's D and C rings are occupied by the flavonoid's A and C rings, respectively.[29][28] Aromatase is encoded and created by a single gene, the CYP19A1[30] and has several promoters that are divided based on where they exist in the body.[31][32] Currently known are I.1 through I.7, and PII promoters[28] which are placenta (I.1) and placental minor (2a) specific, adipose specific (I.3), skin fibroblasts and preadipocytes (I.4), fetal (I.5), bone (I.6), brain (I.f) and endothelial cells (I.7).[33][34][35][36] Although all these promoters vary by region, the encoded mRNA and final protein (aromatase enzyme) are structurally the same.[37]
By aiming for the protein (aromatase), one can induce systemic wide effects. If aiming for protein transcription, one can hopefully induce more controlled effects based on promoter localization.
Genistein, directly on aromatase, can increase its activity as measured in ovarian cells and carcinoma cells.[38][39] It can also stimulate the growth or aromatase in breast cells, and most notable estrogen-responsive breast cancer cells.[40] It can negate the action of pharmaceutical anti-aromatases in these cells.[41][40] In some scenarios, it has been shown to inhibit aromatase directly although it is weak in doing so; isoflavonoids in general are weaker than flavones at aromatase inhibition.[29][42] When acting as an aromatase inhibitor, Genistein has an apparent Ki of 123+/-8uM.[43]
Genistein, working through promoters, can suppress the adipose specific aromatase via I.3[44] and in estrogen-non responsive breast cancers via the same promoter.[28] At times, however, it has been shown to increase activity of this promoter in HepG2 cells and subsequently induce aromatase.[45] It has been noted to reduce transcription in granulosa-luteal cells,[46] and is synergistic with both Daidzein and Biochanin A in this regard.
3.
Neurology
3.1
Serotonergic Neurotransmission
One study investigating phytonutrients able to act as SSRIs noted that both genistein and daidzin were able to inhibit some degree of serotonin reuptake (11.5+/-11.6% and 5.7+/-6.7% respectively) at 50uM, but were unreliable and both much weaker than the active control of Imipramine (74.5+/-11.3% at 5uM).[47]
It is unlikely that soy acts as an SSRI due to the high concentration required and low potency thereof even at these impractical doses
4.
Cardiovascular Health
5.
Interactions with Glucose Metabolism
5.1
Type II Diabetes
Numerous in vivo animal studies have linked Genistein consumption with a decreased fasting blood glucose in already diabetic animal models.[50][51][52] The mechanism of action is hypothesized to be via acting on PI3K, an intermediate in insulin signalling cascades, and does so at concentrations of 10-50uM under conditions of normal glucose and 30uM under conditions of high glucose and was inhibited by introduction of an O-GlcNAcase inhibitor, suggesting another possible mechanism of action via decreasing O-GlcNAcylation.[53]
6.
Fat Mass and Obesity
6.1
Adipogenesis
Genistein appears to inhibit adipogenesis as well as induce fat cell apoptosis via AMP-Actiated protein Kinase (AMPK)[54][53] and appears to be mediated through Reactive-Oxygen Species (ROS) release and was inhibited with treatment of an anti-oxidant.[54][55]
Genistein can also inhibit GLUT4-mediated glucose uptake in adipocytes.[56] Although genistein has the properties of a tyrosine-kinase protein inhibitor[57] (of which the insulin receptor constitutes) the effects from Genistein are independent of direct receptor inhibition.[56][58] These effects were seen best at a concentration of 20uM.
7.
Bone Mass and the Skeleton
7.1
Bone Mass
The anti-osteoporotic effects of Genistein are highly mediated via the ERa receptor (proliferative subset) and are drastically augmented with forms of mechanical resistance (exercise).[59]
8.
Inflammation and Immunology
8.1
Allergies
The high affinity immunoglobulin E (IgE) receptor FcεRI (usually a tetrameric receptor with an α and β subunit with two γ subunits[60]) is involved in mast cell degranulation, since the ligand (IgE) binds to an α subunit which is a mandatory step[61] (γ carries the signal into the cell and β, which is not mandatory, amplifies it[62]) which causes allergic reactions in mast cells. The soy isoflavones can reduce FcεRIα expression after 24 hours of incubation at 5µM or higher, secondary to reducing mRNA transcription (genistein slightly reduced FcεRIβ expression, while daidzein and equol suppressed FcεRIγ) in a manner that is not related to ERK1/2 phosphorylation (the reduction thereof is associated with how green tea catechins are anti-allergic[63]) nor estrogen.[64]
Physiologically relevant concentrations of the soy isoflavones are known to suppress the receptor levels of FcεRI (all three subunit types), which are thought to reduce the amount of signalling into mast cells and thus reduce allergic reactions; this is not related to estrogenic signalling
Atopic disease tends to have FcεRIβ involved in its pathology[65] and due to genistein suppressing FcεRIβ mRNA levels in vitro[64] it may explain the benefits to NC/Nga mice (a model for atopic dermatitis) given 4-20mg/kg genistein daily for eight weeks since IgE and IL-4 concentrations are not affected (although the higher dose attenuated IFN-γ somewhat).[66]
Animal research suggests that genistein may be of use to chronic dermatitis symptoms with daily ingestion with reasonable oral dosages
9.
Interactions with Hormones
9.1
Estrogen
In regards to the alpha subset of the receptor (ERα), the isoflavones can bind to and activate signalling. Genistein has an affinity of 360nM[67] (about 1% that of estrogen itself[45]) and an EC50 of 15μM[68] whereas daidzein has an affinity of 3μM[67] and an EC50 of over 300μM.[68] Equol seems to have an affinity similar to genistein[69] and an EC50 of 3.5μM,[68] which is the most potent of the isoflavones but still less than estrogen itself (as 17β-estradiol at 30nM).
While they are inhernetly agonistic yet weaker than estrogen, it seems that they have the ability to active this receptor when concentrations of estrogen are low yet antagonize this receptor's activation at higher concentrations of estrogen via outcompeting it.[70][71]
The soy isoflavones can signal through the alpha subset of the estrogen recepor (ERα) which is associated with the classical effects of estrogen. They are all weaker than estrogen itself (equol being the most potent) and while they activate this receptor in the absence of estrogen they can competitively inhibit it at higher estrogen concentrations
The three main isoflavones are known to bind to the beta-subunit of the estrogen receptor (ERβ) with genistein having the greatest affinity at 9nM[67] and binding with a potency comparable or greater than estrogen,[69][72] daidzein has the second highest affinity at 552nM[67] and glycitein is the poorest binder.[69] The glycosides of these isoflavones are poor binders[69] and the ability of the aglycones to activate the receptors occurs at relatively low concentrations with an EC50 of 30nM for genistein (17β-estradiol at 10nM[68] and dihydrogenistein equally potent as genistein[69]), daidzein (350nM),[68] and equol (400nM).[68]
The isoflavones are thought to be selective for this subset, since the affinity for this receptor is significantly higher than that of the alpha subset with 40-fold increased affintiy (genistein) and 5-fold (daidzein)[73] and the signalling potency is significantly greater as well at 8.8-fold selectivity (equol), 500-fold (genistein) and over 800-fold (daidzein).[68] Glycitein has been reported to also activate this receptor.[69]
1μM of these isoflavones, sufficient to activate the receptor, seem to work in an additive manner with estrogen.[74]
When looking at the beta subunit of the receptor (ERβ), the soy isoflavones appear to potently activate the receptor at concentrations comparable to estrogen and it does not appear that the antagonism seen with the alpha subunit extends to ERβ. Soy isoflavones are direct and effective agonists of ERβ in the nanomolar range
9.2
Testosterone
Oral intake of genistein at 10mg/kg in male rats has been noted to possess antiandrogenic activity in the testis, prostate, and brain (50-80% reductions in reporter activity) which failed to be antiandrogenic in skeletal muscle or lung tissue.[1] It has been noted to reduce protein content of the androgen receptor itself at 1-50µM in prostate cells (increasing receptor ubiquination)[75] but 10mg/kg for five days in rats failed to replicate this.[1]
In castrated rats, 10mg/kg is able to activate androgen reporter activity in the testes and brain (2.6 and 2.7-fold higher than baseline) and without influence on skeletal muscle or prostate.[1]
When looking at the androgen receptor, it appears that genistein may negatively regulate it in the presence of androgens yet positively regulate it in the absence thereof; it also shows Selective Androgen Receptor Modulator (SARM) properties due to not being active in lungs or skeletal muscle
Genistein is an inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD) via competing with pregnenolone for binding (competitive) and via inhibiting the NAD+ activation of the enzyme.[76] It also can inhibit 17β-HSD with an IC50 of 85+/-15nM[77] and the inhibition on 3β-HSD has been replicated[78][79][80] and does not extend to suppressing the actual expression of 3β-HSD mRNA or its protein content.[81]
When looking at the 5α-reductase enzyme, Genistein and Equol can inhibit the enzyme with an IC50 of 710μM and 370μM respectively while daidzein is ineffective; both underperforming relative to the active control of riboflavin (17μM).[82]
When looking at the enzymes of testosterone synthesis, genistein may inhibit the hydroxysteroid dehydrogenases and secondary to that very high doses may be anti-fertility and anti-androgenic. The inhibitory effects on 5α-reductase are likely not relevant due to the high concentration needed
The aforementioned impairment of enzymatic activity may cause developmental impairment in rat pups (10uM in vitro)[83][84] which is equivalent to a human dose of 100mg/kg.
In rats given 40mg/kg genistein, serum testosterone trended to be reduced (nonsignificant) while 10mg/kg was without affect.[77]
9.3
Luteinizing Hormone
40mg/kg genistein (but not 10mg/kg) to rats is able to increase circulating LH by 29%.[77]
9.4
Follicle-Stimulating Hormone
10-40mg/kg genistein is unable to influence circulating FSH in rats over the course of 21 days.[77]
9.5
Cortisol
Genistein is able to inhibit cortisol synthesis (induced by ACTH) in adrenal cells with an IC50 in the range of 1-4µM with near complete suppression at 40µM, which is due to inhibiting the P450c21 enzyme and preventing the conversion of 17α-hydroxyprogesterone to 11-deoxycortisol.[81]
While 10mg/kg was ineffective, 40mg/kg of genistein for 21 days in rats is able to half serum corticosterone while ACTH is unaffected.[77]
9.6
Dehydroepiandrosterone
It appears that genistein and daidzein can stimulate DHEA and DHEA-S production in isolate adrenal cells with an EC50 value in the range of 1-4µM[81] probably related to its estrogenic properties as estrogen itself can stimulate DHEA production in this tissue.[85]
The inhibition of cortisol from genistein in adrenal tissue is due to inhibition of P450c21,[81] and it is thought that the backlog of the immediate metabolite (17α-hydroxyprogesterone) causes a relative increase in how much substrate is available for DHEA synthesis.[81]
10.
Interactions with Organ Systems
10.1
Adrenal Glands
In isolated adrenaocorticol cells genistein and daidzein appear to be able to suppress ACTH-induced cortisol synthesis with an EC50 in the range of 1-4µM and 40µM suppressing cortisol to near basal levels, and this is mimicked by estrogen[81] which is known to suppress cortisol production.[85] DHEA production in isolated adrenal cells appears to be stimulated with genistein or daidzein with an EC50 in the range of 1-4µM[81] which is also seen with estrogen,[85] and since both cortisol and DHEA are synthesized from the same parent molecule (pregnenolone) which is thought to be due to inhibition of P450c21 (converts 17α-hydroxyprogesterone to 11-deoxycortisol[86]) causing a partitioning effect of 17α-hydroxyprogesterone from cortisol towards DHEA.[81] This property (P450c21 inhibition) is shared with Apigenin[87] and due to the inhibition of 3β-HSD from soy isoflavones there is also a decrease in androstenedione synthesis in the adrenals.[87]
Genistein appears to inhibit P450c21 in the adrenal glands, which causes a reduction in cortisol and relative increase in DHEA synthesis. Androstenedione also appears to be reduced
Concentrations of up to 40µM are not toxic to adrenal cells.[81]
10.2
Testicles
When looking at the weight and histology of the testicles in genistein fed rats, they appear to be normal suggesting no toxic properties.[77]
11.
Interactions with Cancer Metabolism
11.1
Breast Cancer
Genistein is most notably in its effects against Breast Cancer. It (Soy intake) has been correlated with a reduced risk of breast cancer in numerous epidemiological studies.
Genistein appears to act as a pro-carcinogen in breast cancer lines that express Estrogen Receptor Alpha (ERa) predominately at normal doses (6-8uM), although in supra-physiological doses (more than 10uM) this effect is reversed.[88][89][57][90]
11.2
Prostate Cancer
In regards to prostate cancer, genistein (via soy intake) has been implicated in epidemiological studies to be associated with a decreased risk of prostate cancer.[91][92] This is somewhat backed up by lower rates of prostate cancer in Asian countries relative to Western countries with lower soy intakes[93][1] paired with asian immigrants matching western rates of prostate cancer upon immigration.[94]
In vitro results suggest that genistein can act via inhibiting NF-kB in various cells[95] and suppression of metalloproteins associated with cancer.[96] Other possible mechanisms of action include preventing an upregulation in 5a-reductase activity in the prostate from a high-fat diet.[97]
These results have been applied to animal models showing genistein intervention capable of reducing prostate cancer metastasis[98] and acting as an anti-carcinogen.[98]
Via AMPK activation[54], Genistein can aid in regulating a cell cycle's lifespan.[99][100]
12.
Nutrient-Nutrient Interactions
12.1
Breast Cancer Drugs
Tamoxifen is a pharmaceutical anti-estrogen that directly competes with estrogen at the level of the receptor and is commonly used for the treamtent of breast cancer.[101][102]
1,000ppm genistein in the diet (1%) has been noted to reduce the inhibitory effects of tamoxifen on MCF-7 tumor growth in mice[103] and elsewhere studies using mixed isoflavones (0.22%)[104] or genistein (0.14%)[105] at low doses have found inhibitory effects that were not seen with 0.44% mixed isoflavones.[104] Due to these studies, a study using scaling doses of genistein (0.25-1%; causes circulating levels of 1.4–3.3μM[106]) in tumor bearing mice noted that while 0.25% reduced the effects of tamoxifen and 0.5% abolished it the highest tested dose (1%) failed to inhibit tamoxifen.[41] When looking at daidzein, it appears to enhance the effects of tamoxifen.[105]
The above information is in accordance with the role of genistein in signalling through the alpha subset of the estrogen receptor (ERα) which occurs at low concentrations but not so much at higher concentrations (and which daidzein is a poor activator of). Genistein has been noted to stimulate the growth of breast cancer cells that expresss ERα specifically at physiologically relevant concentrations,[107][90][106] and it is thought that it is outcompeting tamoxifen at the level of the receptor due to its high affinity.
Genistein, but not daidzein, is known to interact with the anti-breast cancer drug tamoxifen (an estrogen receptor antagonist). It is thought that genistein is outcompeting tamoxifen at the level of the receptor, and thus it would be prudent to avoid soy based supplements during tamoxifen therapy
Letrozole is an aromatase inhibiting pharmaceutical that alone is effective in the treatment of breast cancer,[108] and is sometimes used alongside estrogen receptor antagonists such as tamoxifen. Genistein is also an aromatase inhibitor at high concentrations (10μM)[109] but not physiologically relevant concentrations (1μM)[110]
Dietary genistein at 250-1,000ppm of the mouse diet is able to prevent the inhibitory effects of letrozole (aromatase inhibitor) on breast tumor growth in a dose-dependent manner.[40]
May also adversely interact with the anti-breast cancer drug letrozole, an aromatase inhibitor
12.2
Probiotics
As the bacterial conversion of Daidzein to Equol (in Equol producers) appears to be a significant aspect of the estrogenicity of soy products, it was investigated as to whether consumption of probiotics could influence this conversion. Two studies investigating Lactobacillus Acidophillus and Bifidobacterium longum found that oral administration of these probiotics does not alter Equol producing status.[111][112]
13.
Safety and Toxicity
References
- ^The Phytoestrogen Genistein Is a Tissue-Specific Androgen Receptor Modulator
- ^Nakamura Y, Tsuji S, Tonogai YDetermination of the levels of isoflavonoids in soybeans and soy-derived foods and estimation of isoflavonoids in the Japanese daily intakeJ AOAC Int.(2000 May-Jun)
- ^Evaluation of Genistin and Genistein Contents in Soybean Varieties and Soy Protein Concentrate Prepared with 3 Basic Methods
- ^Fukutake M, Takahashi M, Ishida K, Kawamura H, Sugimura T, Wakabayashi KQuantification of genistein and genistin in soybeans and soybean productsFood Chem Toxicol.(1996 May)
- ^Kaufman PB, Duke JA, Brielmann H, Boik J, Hoyt JEA comparative survey of leguminous plants as sources of the isoflavones, genistein and daidzein: implications for human nutrition and healthJ Altern Complement Med.(1997 Spring)
- ^Hamilton-Reeves JM, Rebello SA, Thomas W, Slaton JW, Kurzer MSIsoflavone-rich soy protein isolate suppresses androgen receptor expression without altering estrogen receptor-beta expression or serum hormonal profiles in men at high risk of prostate cancerJ Nutr.(2007 Jul)
- ^Alekel DL, Germain AS, Peterson CT, Hanson KB, Stewart JW, Toda TIsoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal womenAm J Clin Nutr.(2000 Sep)
- ^Huang Q, Huang R, Zhang S, Lin J, Wei L, He M, Zhuo L, Lin XProtective effect of genistein isolated from Hydrocotyle sibthorpioides on hepatic injury and fibrosis induced by chronic alcohol in ratsToxicol Lett.(2013 Feb 27)
- ^Meeran SM, Ahmed A, Tollefsbol TOEpigenetic targets of bioactive dietary components for cancer prevention and therapyClin Epigenetics.(2010 Dec 1)
- ^Increased miroestrol, deoxymiroestrol and isoflavonoid accumulation in callus and cell suspension cultures of Pueraria candollei var. mirifica
- ^Isolation of new isoflavonolignans, Butesuperins A and B, from a Thai miracle herb
- ^Saeed IA, Ali L, Jabeen A, Khasawneh M, Rizvi TA, Ashraf SSEstrogenic activities of ten medicinal herbs from the Middle EastJ Chromatogr Sci.(2013 Jan)
- ^Phytochemical and Biological Studies of plants from the GenusOxytropis
- ^Barnes SThe biochemistry, chemistry and physiology of the isoflavones in soybeans and their food productsLymphat Res Biol.(2010 Mar)
- ^Barnes S, Prasain J, D'Alessandro T, Arabshahi A, Botting N, Lila MA, Jackson G, Janle EM, Weaver CMThe metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systemsFood Funct.(2011 May)
- ^Day AJ, Cañada FJ, Díaz JC, Kroon PA, Mclauchlan R, Faulds CB, Plumb GW, Morgan MR, Williamson GDietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolaseFEBS Lett.(2000 Feb 25)
- ^Esaki H, Shirasaki T, Yamashita K, Nakamura Y, Kawakishi S, Osawa TAbsorption and excretion of the 8-hydroxydaidzein in rats after oral administration and its antioxidant effectJ Nutr Sci Vitaminol (Tokyo).(2005 Apr)
- ^Ahmed AA, Goldsmith J, Fokt I, Le XF, Krzysko KA, Lesyng B, Bast RC Jr, Priebe WA genistein derivative, ITB-301, induces microtubule depolymerization and mitotic arrest in multidrug-resistant ovarian cancerCancer Chemother Pharmacol.(2011 Oct)
- ^Hydrolysis of Isoflavone Glycosides to Aglycones by ß-Glycosidase Does Not Alter Plasma and Urine Isoflavone Pharmacokinetics in Postmenopausal Women
- ^Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women
- ^Decroos K, Vanhemmens S, Cattoir S, Boon N, Verstraete WIsolation and characterisation of an equol-producing mixed microbial culture from a human faecal sample and its activity under gastrointestinal conditionsArch Microbiol.(2005 Jan)
- ^Setchell KD, Cassidy ADietary isoflavones: biological effects and relevance to human healthJ Nutr.(1999 Mar)
- ^Yuan JP, Wang JH, Liu XMetabolism of dietary soy isoflavones to equol by human intestinal microflora--implications for healthMol Nutr Food Res.(2007 Jul)
- ^Rafii F, Davis C, Park M, Heinze TM, Beger RDVariations in metabolism of the soy isoflavonoid daidzein by human intestinal microfloras from different individualsArch Microbiol.(2003 Jul)
- ^The Clinical Importance of the Metabolite Equol—A Clue to the Effectiveness of Soy and Its Isoflavones
- ^Hedlund TE, Johannes WU, Miller GJSoy isoflavonoid equol modulates the growth of benign and malignant prostatic epithelial cells in vitroProstate.(2003 Jan 1)
- ^Simpson ERAromatase: biologic relevance of tissue-specific expressionSemin Reprod Med.(2004 Feb)
- ^Khan SI, Zhao J, Khan IA, Walker LA, Dasmahapatra AKPotential utility of natural products as regulators of breast cancer-associated aromatase promotersReprod Biol Endocrinol.(2011 Jun 21)
- ^Kao YC, Zhou C, Sherman M, Laughton CA, Chen SMolecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis studyEnviron Health Perspect.(1998 Feb)
- ^Means GD, Mahendroo MS, Corbin CJ, Mathis JM, Powell FE, Mendelson CR, Simpson ERStructural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesisJ Biol Chem.(1989 Nov 15)
- ^Bulun SE, Simpson ERAromatase expression in women's cancersAdv Exp Med Biol.(2008)
- ^Jiao J, Xiang H, Liao QRecent advancement in nonsteroidal aromatase inhibitors for treatment of estrogen-dependent breast cancerCurr Med Chem.(2010)
- ^Mahendroo MS, Means GD, Mendelson CR, Simpson ERTissue-specific expression of human P-450AROM. The promoter responsible for expression in adipose tissue is different from that utilized in placentaJ Biol Chem.(1991 Jun 15)
- ^Chen D, Reierstad S, Lu M, Lin Z, Ishikawa H, Bulun SERegulation of breast cancer-associated aromatase promotersCancer Lett.(2009 Jan 8)
- ^Simpson ER, Michael MD, Agarwal VR, Hinshelwood MM, Bulun SE, Zhao YCytochromes P450 11: expression of the CYP19 (aromatase) gene: an unusual case of alternative promoter usageFASEB J.(1997 Jan)
- ^Sebastian S, Takayama K, Shozu M, Bulun SECloning and characterization of a novel endothelial promoter of the human CYP19 (aromatase P450) gene that is up-regulated in breast cancer tissueMol Endocrinol.(2002 Oct)
- ^Bulun SE, Takayama K, Suzuki T, Sasano H, Yilmaz B, Sebastian SOrganization of the human aromatase p450 (CYP19) geneSemin Reprod Med.(2004 Feb)
- ^Sanderson JT, Hordijk J, Denison MS, Springsteel MF, Nantz MH, van den Berg MInduction and inhibition of aromatase (CYP19) activity by natural and synthetic flavonoid compounds in H295R human adrenocortical carcinoma cellsToxicol Sci.(2004 Nov)
- ^Myllymäki S, Haavisto T, Vainio M, Toppari J, Paranko JIn vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian folliclesToxicol Appl Pharmacol.(2005 Apr 1)
- ^Ju YH, Doerge DR, Woodling KA, Hartman JA, Kwak J, Helferich WGDietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivoCarcinogenesis.(2008 Nov)
- ^Du M, Yang X, Hartman JA, Cooke PS, Doerge DR, Ju YH, Helferich WGLow-dose dietary genistein negates the therapeutic effect of tamoxifen in athymic nude miceCarcinogenesis.(2012 Jan 20)
- ^Pelissero C, Lenczowski MJ, Chinzi D, Davail-Cuisset B, Sumpter JP, Fostier AEffects of flavonoids on aromatase activity, an in vitro studyJ Steroid Biochem Mol Biol.(1996 Feb)
- ^Kim YW, Hackett JC, Brueggemeier RWSynthesis and aromatase inhibitory activity of novel pyridine-containing isoflavonesJ Med Chem.(2004 Jul 29)
- ^Wang Y, Man Gho W, Chan FL, Chen S, Leung LKThe red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expressionBr J Nutr.(2008 Feb)
- ^Ye L, Chan MY, Leung LKThe soy isoflavone genistein induces estrogen synthesis in an extragonadal pathwayMol Cell Endocrinol.(2009 Apr 10)
- ^Rice S, Mason HD, Whitehead SAPhytoestrogens and their low dose combinations inhibit mRNA expression and activity of aromatase in human granulosa-luteal cellsJ Steroid Biochem Mol Biol.(2006 Nov)
- ^Ofir R, Tamir S, Khatib S, Vaya JInhibition of serotonin re-uptake by licorice constituentsJ Mol Neurosci.(2003 Apr)
- ^Scheiber MD, Liu JH, Subbiah MT, Rebar RW, Setchell KDDietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal womenMenopause.(2001 Sep-Oct)
- ^Sirtori CRRisks and benefits of soy phytoestrogens in cardiovascular diseases, cancer, climacteric symptoms and osteoporosisDrug Saf.(2001)
- ^Genistein and daidzein modulate hepatic glucose and lipid regulating enzyme activities in C57BL/KsJ-db/db mice
- ^Lee JSEffects of soy protein and genistein on blood glucose, antioxidant enzyme activities, and lipid profile in streptozotocin-induced diabetic ratsLife Sci.(2006 Sep 13)
- ^Soy Isoflavones Exert Antidiabetic and Hypolipidemic Effects through the PPAR Pathways in Obese Zucker Rats and Murine RAW 264.7 Cells
- ^Ha BG, Nagaoka M, Yonezawa T, Tanabe R, Woo JT, Kato H, Chung UI, Yagasaki KRegulatory mechanism for the stimulatory action of genistein on glucose uptake in vitro and in vivoJ Nutr Biochem.(2011 Jun 16. {Epub ahead of print}di)
- ^Hwang JT, Park IJ, Shin JI, Lee YK, Lee SK, Baik HW, Ha J, Park OJGenistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinaseBiochem Biophys Res Commun.(2005 Dec 16)
- ^Qanungo S, Das M, Haldar S, Basu AEpigallocatechin-3-gallate induces mitochondrial membrane depolarization and caspase-dependent apoptosis in pancreatic cancer cellsCarcinogenesis.(2005 May)
- ^Bazuine M, van den Broek PJ, Maassen JAGenistein directly inhibits GLUT4-mediated glucose uptake in 3T3-L1 adipocytesBiochem Biophys Res Commun.(2005 Jan 14)
- ^Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami YGenistein, a specific inhibitor of tyrosine-specific protein kinasesJ Biol Chem.(1987 Apr 25)
- ^Smith RM, Tiesinga JJ, Shah N, Smith JA, Jarett LGenistein inhibits insulin-stimulated glucose transport and decreases immunocytochemical labeling of GLUT4 carboxyl-terminus without affecting translocation of GLUT4 in isolated rat adipocytes: additional evidence of GLUT4 activation by insulinArch Biochem Biophys.(1993 Jan)
- ^Hertrampf T, Gruca MJ, Seibel J, Laudenbach U, Fritzemeier KH, Diel PThe bone-protective effect of the phytoestrogen genistein is mediated via ER alpha-dependent mechanisms and strongly enhanced by physical activityBone.(2007 Jun)
- ^The High-Afintiy IgE Receptor (FcεRI): From Physiology to Pathology
- ^Dombrowicz D, Flamand V, Brigman KK, Koller BH, Kinet JPAbolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor alpha chain geneCell.(1993 Dec 3)
- ^The FcεRIβ Subunit Functions as an Amplifier of FcεRIγ-Mediated Cell Activation Signals
- ^Antiallergic Tea Catechin, (−)-Epigallocatechin-3-O-(3-O-methyl)-gallate, Suppresses FcεRI Expression in Human Basophilic KU812 Cells
- ^Yamashita S, Tsukamoto S, Kumazoe M, Kim YH, Yamada K, Tachibana HIsoflavones Suppress the Expression of the FcεRI High-Affinity Immunoglobulin E Receptor Independent of the Estrogen ReceptorJ Agric Food Chem.(2012 Aug 16)
- ^Sandford AJ, Shirakawa T, Moffatt MF, Daniels SE, Ra C, Faux JA, Young RP, Nakamura Y, Lathrop GM, Cookson WO, et alLocalisation of atopy and beta subunit of high-affinity IgE receptor (Fc epsilon RI) on chromosome 11qLancet.(1993 Feb 6)
- ^Sakai T, Kogiso M, Mitsuya K, Komatsu T, Yamamoto SGenistein suppresses development of spontaneous atopic-like dermatitis in NC/Nga miceJ Nutr Sci Vitaminol (Tokyo).(2006 Aug)
- ^Manas ES, Xu ZB, Unwalla RJ, Somers WSUnderstanding the selectivity of genistein for human estrogen receptor-beta using X-ray crystallography and computational methodsStructure.(2004 Dec)
- ^Kostelac D, Rechkemmer G, Briviba KPhytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response elementJ Agric Food Chem.(2003 Dec 17)
- ^Morito K, Hirose T, Kinjo J, Hirakawa T, Okawa M, Nohara T, Ogawa S, Inoue S, Muramatsu M, Masamune YInteraction of phytoestrogens with estrogen receptors alpha and betaBiol Pharm Bull.(2001 Apr)
- ^Hwang CS, Kwak HS, Lim HJ, Lee SH, Kang YS, Choe TB, Hur HG, Han KOIsoflavone metabolites and their in vitro dual functions: they can act as an estrogenic agonist or antagonist depending on the estrogen concentrationJ Steroid Biochem Mol Biol.(2006 Nov)
- ^Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor alpha (ERalpha) and ERbeta in human cells
- ^Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JAInteraction of estrogenic chemicals and phytoestrogens with estrogen receptor betaEndocrinology.(1998 Oct)
- ^Harris HA, Bapat AR, Gonder DS, Frail DEThe ligand binding profiles of estrogen receptors alpha and beta are species dependentSteroids.(2002 Apr)
- ^Amer DA, Kretzschmar G, Müller N, Stanke N, Lindemann D, Vollmer GActivation of transgenic estrogen receptor-beta by selected phytoestrogens in a stably transduced rat serotonergic cell lineJ Steroid Biochem Mol Biol.(2010 Jun)
- ^Basak S, Pookot D, Noonan EJ, Dahiya RGenistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone functionMol Cancer Ther.(2008 Oct)
- ^Hu GX, Zhao BH, Chu YH, Zhou HY, Akingbemi BT, Zheng ZQ, Ge RSEffects of genistein and equol on human and rat testicular 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase 3 activitiesAsian J Androl.(2010 Jul)
- ^Ohno S, Nakajima Y, Inoue K, Nakazawa H, Nakajin SGenistein administration decreases serum corticosterone and testosterone levels in ratsLife Sci.(2003 Dec 26)
- ^Flavonoid inhibition of overexpressed human 3β-hydroxysteroid dehydrogenase type II
- ^Dose–response effects of phytoestrogens on the activity and expression of 3β-hydroxysteroid dehydrogenase and aromatase in human granulosa-luteal cells
- ^Effects of phytoestrogens on aromatase, 3β and 17β-hydroxysteroid dehydrogenase activities and human breast cancer cells
- ^Mesiano S, Katz SL, Lee JY, Jaffe RBPhytoestrogens alter adrenocortical function: genistein and daidzein suppress glucocorticoid and stimulate androgen production by cultured adrenal cortical cellsJ Clin Endocrinol Metab.(1999 Jul)
- ^Bae M, Woo M, Kusuma IW, Arung ET, Yang CH, Kim YUInhibitory effects of isoflavonoids on rat prostate testosterone 5α-reductaseJ Acupunct Meridian Stud.(2012 Dec)
- ^Lehraiki A, Chamaillard C, Krust A, Habert R, Levacher CGenistein impairs early testosterone production in fetal mouse testis via estrogen receptor alphaToxicol In Vitro.(2011 Dec)
- ^Laurenzana EM, Weis CC, Bryant CW, Newbold R, Delclos KBEffect of dietary administration of genistein, nonylphenol or ethinyl estradiol on hepatic testosterone metabolism, cytochrome P-450 enzymes, and estrogen receptor alpha expressionFood Chem Toxicol.(2002 Jan)
- ^Mesiano S, Jaffe RBInteraction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate productionJ Clin Endocrinol Metab.(1993 Sep)
- ^Mizrachi D, Wang Z, Sharma KK, Gupta MK, Xu K, Dwyer CR, Auchus RJWhy human cytochrome P450c21 is a progesterone 21-hydroxylaseBiochemistry.(2011 May 17)
- ^Hasegawa E, Nakagawa S, Sato M, Tachikawa E, Yamato SEffect of polyphenols on production of steroid hormones from human adrenocortical NCI-H295R cellsBiol Pharm Bull.(2013)
- ^Chang EC, Charn TH, Park SH, Helferich WG, Komm B, Katzenellenbogen JA, Katzenellenbogen BSEstrogen Receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin bindingMol Endocrinol.(2008 May)
- ^Allred CD, Allred KF, Ju YH, Virant SM, Helferich WGSoy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent mannerCancer Res.(2001 Jul 1)
- ^Wang TT, Sathyamoorthy N, Phang JMMolecular effects of genistein on estrogen receptor mediated pathwaysCarcinogenesis.(1996 Feb)
- ^Yan L, Spitznagel ELSoy consumption and prostate cancer risk in men: a revisit of a meta-analysisAm J Clin Nutr.(2009 Apr)
- ^Andres S, Abraham K, Appel KE, Lampen ARisks and benefits of dietary isoflavones for cancerCrit Rev Toxicol.(2011 Jul)
- ^Global Cancer Statistics, 2002
- ^Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, Mack TMCancers of the prostate and breast among Japanese and white immigrants in Los Angeles CountyBr J Cancer.(1991 Jun)
- ^Li Y, Ahmed F, Ali S, Philip PA, Kucuk O, Sarkar FHInactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cellsCancer Res.(2005 Aug 1)
- ^Kousidou OC, Mitropoulou TN, Roussidis AE, Kletsas D, Theocharis AD, Karamanos NKGenistein suppresses the invasive potential of human breast cancer cells through transcriptional regulation of metalloproteinases and their tissue inhibitorsInt J Oncol.(2005 Apr)
- ^Cai LQ, Cai J, Wu W, Zhu YS17α-Estradiol and genistein inhibit high fat diet induced prostate gene expression and prostate growth in the ratJ Urol.(2011 Oct)
- ^Genistein chemoprevention of prostate cancer in TRAMP mice
- ^Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CBAMP-activated protein kinase induces a p53-dependent metabolic checkpointMol Cell.(2005 Apr 29)
- ^Meisse D, Van de Casteele M, Beauloye C, Hainault I, Kefas BA, Rider MH, Foufelle F, Hue LSustained activation of AMP-activated protein kinase induces c-Jun N-terminal kinase activation and apoptosis in liver cellsFEBS Lett.(2002 Aug 28)
- ^Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trialsLancet.(2005 May 14-20)
- ^Osborne CKTamoxifen in the treatment of breast cancerN Engl J Med.(1998 Nov 26)
- ^Ju YH, Doerge DR, Allred KF, Allred CD, Helferich WGDietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic miceCancer Res.(2002 May 1)
- ^Liu B, Edgerton S, Yang X, Kim A, Ordonez-Ercan D, Mason T, Alvarez K, McKimmey C, Liu N, Thor ALow-dose dietary phytoestrogen abrogates tamoxifen-associated mammary tumor preventionCancer Res.(2005 Feb 1)
- ^Constantinou AI, White BE, Tonetti D, Yang Y, Liang W, Li W, van Breemen RBThe soy isoflavone daidzein improves the capacity of tamoxifen to prevent mammary tumoursEur J Cancer.(2005 Mar)
- ^Ju YH, Allred CD, Allred KF, Karko KL, Doerge DR, Helferich WGPhysiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude miceJ Nutr.(2001 Nov)
- ^Zava DT, Duwe GEstrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitroNutr Cancer.(1997)
- ^Mouridsen H, Gershanovich M, Sun Y, Pérez-Carrión R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jänicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, Chaudri-Ross HA, Dugan MSuperior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer GroupJ Clin Oncol.(2001 May 15)
- ^Foster BC, Vandenhoek S, Hana J, Krantis A, Akhtar MH, Bryan M, Budzinski JW, Ramputh A, Arnason JTIn vitro inhibition of human cytochrome P450-mediated metabolism of marker substrates by natural productsPhytomedicine.(2003 May)
- ^Almstrup K, Fernández MF, Petersen JH, Olea N, Skakkebaek NE, Leffers HDual effects of phytoestrogens result in u-shaped dose-response curvesEnviron Health Perspect.(2002 Aug)
- ^McMullen MH, Hamilton-Reeves JM, Bonorden MJ, Wangen KE, Phipps WR, Feirtag JM, Kurzer MSConsumption of Lactobacillus acidophilus and Bifidobacterium longum does not alter phytoestrogen metabolism and plasma hormones in men: a pilot studyJ Altern Complement Med.(2006 Nov)
- ^Bonorden MJ, Greany KA, Wangen KE, Phipps WR, Feirtag J, Adlercreutz H, Kurzer MSConsumption of Lactobacillus acidophilus and Bifidobacterium longum do not alter urinary equol excretion and plasma reproductive hormones in premenopausal womenEur J Clin Nutr.(2004 Dec)