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PubMed2005

High concordance of daidzein-metabolizing phenotypes in individuals measured 1 to 3 years apart.

Particular intestinal bacteria are capable of metabolizing the soya isoflavone daidzein to equol and/or O-desmethylangolensin (O-DMA), and the presence of these metabolites in urine after soya consumption are markers of particular intestinal bacteria profiles. Prevalences of equol producers and O-DMA producers are approximately 30-50 % and 80-90 %, respectively, and limited observations have suggested that these daidzein-metabolizing phenotypes are stable within individuals over time. Characterizing stability of these phenotypes is important to understand their potential as markers of long-term exposure to particular intestinal bacteria and their associations with disease risk. We evaluated concordance within an individual for the equol-producer and O-DMA-producer phenotypes measured at two time points (T1, T2), 1-3 years apart. Phenotypes were ascertained by analysing equol and O-DMA using GC-MS in a spot urine sample collected after 3 d soya (source of daidzein) supplementation. In ninety-two individuals without recent (within 3 months before phenotyping) or current antibiotics use, 41 % were equol producers at T1 and 45 % were equol producers at T2, and 90 % were O-DMA producers at T1 and 95 % were O-DMA producers at T2. The percentage agreement for the equol-producer phenotype was 82 and for the O-DMA-producer phenotype was 89. These results indicate that these phenotypes are stable in most individuals over time, suggesting that they provide a useful biomarker for evaluating disease risk associated with harbouring particular intestinal bacteria responsible for, or associated with, the metabolism of the soya isoflavone daidzein.

Anti-Bacterial Agents↗
PubMed2006

Detection of isoflavones in mouse tibia after feeding daidzein.

Many studies suggest that diets rich in isoflavones protect against bone loss or slow the loss of bone mass that occurs because of estrogen withdrawal. Although in vitro studies have reported effects of isoflavones on bone cells, the presence of daidzein and/or equol in bone tissue in vivo has not been reported. The objective of this study was to determine if daidzein and equol were present in bone tissue (tibias) after feeding mice a diet containing purified daidzein. Sham mice (n = 9) received control diet, and ovariectomized mice were randomized to control diet (Ovx) (n = 9) or control diet containing 200 mg of daidzein/kg of diet (n = 8) for 12 weeks. At necropsy, tibias and serum were collected. Mice in the Daidzein group had significantly higher (P < .05) levels of both daidzein and equol in tibias than Sham and Ovx mice. Tibia levels of daidzein and equol were approximately five and four times higher, respectively, than the Sham and Ovx groups. Similarly, mice fed daidzein also had significantly higher (P < .05) serum daidzein and equol than the Sham and Ovx mice. In conclusion, feeding a level of daidzein that is attainable by dietary intervention alone results in a high level of both daidzein and equol in tibias. These findings suggest that daidzein and its metabolite, equol, have the potential to act directly on bone cells in vivo.

Animals↗
PubMed2006

Prevalence of daidzein-metabolizing phenotypes differs between Caucasian and Korean American women and girls.

Interindividual differences in metabolism of the soy isoflavone, daidzein, to equol and O-desmethylangolensin (ODMA) by human gut bacteria, have been associated with altered risk of cancer and other chronic diseases, according to some studies. Differences have been reported in the prevalence of the equol-producer phenotype among populations, with a higher prevalence in soy-consuming Asian populations than in Western populations. To date, prevalence of the daidzein-metabolizing phenotypes in Asians, compared with Caucasians, has not been evaluated in the context of a standardized phenotyping method. We assessed the prevalence of equol- and ODMA-producer phenotypes in 91 Korean American (KA) women and girls living in the Seattle, Washington area and compared this with previous similarly collected prevalence data in Caucasian American (CA) women and girls (n = 222). We also compared the dietary habits of the 2 groups. Isoflavonoid concentrations in first-void morning urines, collected after a 3-d soy challenge, were used to establish equol-, and ODMA-producer phenotypes (>44 microg/L). The prevalence of the equol-producer phenotype was higher (51 vs. 36%; P = 0.015) and the ODMA-producer phenotype was lower (84 vs. 92%, P = 0.03) in KA than in CA women and girls. KAs consumed approximately 3 times more soy foods than the CAs, but no significant associations were found between the consumption of soy foods and equol-producer phenotype. Our findings support the reports that, compared with Western populations, Asian populations have a higher equol-producer prevalence. The additional observation that the prevalence of the ODMA-producer phenotype is lower in KAs suggests that daidzein-metabolizing patterns in general may differ between KAs and CAs.

Adult↗
PubMed2004

Familial correlations, segregation analysis, and nongenetic correlates of soy isoflavone-metabolizing phenotypes.

Particular intestinal bacteria metabolize the soy isoflavone daidzein to equol and O-desmethylangolensin (O-DMA), metabolites that can be identified in urine. Individuals that harbor bacteria capable of producing equol or O-DMA are known as equol producers (approximately 30%-50% of the population) and O-DMA producers (approximately 80%-90% of the population), respectively. The equol-producer phenotype has been associated with sex hormone-related outcomes in several studies. However, the bacteria responsible for these phenotypes have not yet been identified and factors that influence the manifestation of these phenotypes are not well understood. To evaluate familial clustering of and nongenetic factors associated with these phenotypes, 410 individuals from 112 families participated in phenotyping (3-day soy challenge and Day 4 spot urine collection). In segregation analyses of the equol-producer phenotype, the Mendelian dominant model provided the most parsimonious fit to the data, suggesting that the pattern of inheritance of the equol-producer phenotype is consistent with an autosomal dominant trait. This phenotype was positively associated with education (p trend = 0.01), but not with sex, smoking, or several dietary factors. Results of the segregation analyses of the O-DMA-producer phenotype were inconclusive; no other models provided a more parsimonious fit to the data than the general model. This phenotype was inversely associated with age in a nonlinear model (p = 0.01), positively associated with age- and sex-adjusted height (odds ratio [OR] 10-cm increase = 0.38, 95% confidence interval [CI] = 0.15, 0.95) and body mass index (kg/m(2)) (OR = 0.91, 95% CI = 0.85, 0.96), but not with sex, education, smoking, or several dietary factors. These results suggest the equol-producer phenotype may be under some degree of genetic control and that there are likely other environmental factors not evaluated in the present analysis that contribute to both of these phenotypes. These results provide a foundation for further work to refine our understanding of heritable and environmental determinants of daidzein-metabolizing phenotypes.

Female↗
PubMed2006

Cooperative effects of isoflavones and exercise on bone and lipid metabolism in postmenopausal Japanese women: a randomized placebo-controlled trial.

Cooperative effects of isoflavones and exercise on bone and lipid metabolism have been exhibited in estrogen-deficient animals; however, results from clinical trials have not been published. In this study, we determined the effects of isoflavone intake and walking and their interaction on bone and lipid metabolism in postmenopausal women over 24 weeks. The bioavailability and metabolism of isoflavones (daidzein in particular) were also examined to clarify the mechanism of their bone-protective effects in humans. One hundred twenty-eight subjects were randomly assigned to 4 groups: placebo; placebo combined with walking (3 times per week); isoflavone intake (75 mg of isoflavones conjugates per day); and isoflavone combined with walking. The subjects were classified by equol status (producers or nonproducers) as identified using production of equol from daidzein in fecal culture. Bone mineral density (BMD), body composition, and serum concentrations of isoflavones were assessed. Serum high-density lipoprotein cholesterol concentration significantly increased (6.1%, P = .03), and fat mass in the whole body significantly decreased (-4.3%, P = .0003) from the baseline in the combined intervention group. There were no significant differences in BMD between baseline and postintervention in any of the treatment groups. However, the percent changes in BMD in equol producers were -0.53% and +0.13% in the sub-whole body and total hip, respectively. This was significantly different compared with -1.35 and -1.77 for the sub-whole body and total hip, respectively, in nonproducers in the isoflavone group (P = .049 and .040, respectively). The mean serum equol concentration was significantly higher in equol producers than in nonproducers in the isoflavone groups, but not in the placebo group. The combination of isoflavones and exercise exhibited favorable effects on serum lipid and body composition of postmenopausal women. The findings of this study suggest that the preventive effects of isoflavones on bone loss depend on the individual's intestinal flora for equol production.

Asian People↗
PubMed2005

Polymorphisms in the CYP19 gene may affect the positive correlations between serum and urine phytoestrogen metabolites and plasma androgen concentrations in men.

Phytoestrogens have been hypothesized to protect against prostate cancer via modulation of circulating androgen concentrations. We conducted a cross-sectional study of 267 men in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with 2 aims: first, to investigate the association between phytoestrogen exposure (measured from diet, urine, and serum) and plasma concentrations of sex hormone-binding globulin (SHBG), androstanediol glucuronide, testosterone and Free Androgen Index (FAI); and second, whether the association may be modified by polymorphisms in CYP19 and SHBG genes. Dietary daidzein and genistein intakes were obtained from food diaries and computed using an in-house food composition database. Urinary and serum concentrations of 3 isoflavones (daidzein, genistein, glycitein), 2 daidzein metabolites O-desmethylangolensin (O-DMA) and 2 lignan metabolites (enterodiol and enterolactone) were measured using mass spectrometry. There was no association between dietary, urinary, and serum phytoestrogens and plasma SHBG concentrations. Enterolactone was positively associated with plasma androstanediol glucuronide concentrations (urinary enterolactone: r = 0.127, P = 0.043; serum enterolactone: r = 0.172, P = 0.006) and FAI (urinary enterolactone: r = 0.115, P = 0.067; serum enterolactone: r = 0.158, P = 0.011). Both urinary and serum equol were associated with plasma testosterone (urinary equol: r = 0.332, P = 0.013; serum equol: r = 0.318, P = 0.018) and FAI (urinary equol: r = 0.297, P = 0.027; serum equol: r = 0.380, P = 0.004) among men with the TT genotype but not the CC or CT genotypes (r = -0.029 to -0.134, P = 0.091-0.717) for the CYP19 3'untranslated region (UTR) T-C polymorphism. Urinary and serum enterolactone showed similar genotype-dependent associations with testosterone but not with FAI. In this first study on phytoestrogen-gene associations in men, we conclude that enterolactone and equol are positively associated with plasma androgen concentrations, and interactions with CYP19 gene may be involved.

4-Butyrolactone↗
PubMed2005

Long-term dietary habits affect soy isoflavone metabolism and accumulation in prostatic fluid in caucasian men.

The soy isoflavones daidzein and genistein are believed to reduce prostate cancer risk in soy consumers. However, daidzein can be metabolized by the intestinal flora to form a variety of compounds with different bioactivities. In the current study, we investigated the influence of long-term dietary habits on daidzein metabolism in healthy Caucasian men (19-65 y old). A secondary goal was to compare plasma and prostatic fluid concentrations of 5 isoflavonoids: genistein, daidzein, equol, dihydrodaidzein, and O-desmethylangolensin. Baseline plasma levels of isoflavonoids were quantitated in 45 men by HPLC-electrospray ionization-MS. Participants then consumed a soy beverage daily for 1 wk, and post-soy isoflavonoid levels were quantitated in plasma and prostatic fluid. Equol was the only metabolite that appeared to be influenced by routine dietary habits. Stratified analyses revealed that men who had consumed > or =30 mg soy isoflavones/d for at least 2 y had 5.3-times the probability of producing equol than men who had consumed < or =5 mg/d (P = 0.014). Additionally, those men who consumed animal meat regularly had 4.7-times the probability of producing equol than men who did not consume meat (P = 0.023). Equol production was not linked to age, BMI, or the consumption of yogurt, dairy, fruit, or American-style fast food. Daidzein and its metabolites (but not genistein) were typically present at higher levels in prostate fluid than plasma (median = 4-13 times that in plasma). In conclusion, our data suggest that the ability of Caucasian men to produce equol is favorably influenced by the long-term consumption of high amounts of soy and the consumption of meat. Last, the high concentrations of isoflavonoids in prostatic fluid increases the potential for these compounds to have direct effects in the prostate.

Adult↗
PubMed2003

Soy-derived isoflavones exert opposing actions on Guinea pig ventricular myocytes.

Soy-derived isoflavones appear to possess cardioprotective properties, although the precise nature of this protection and the particular isoflavones responsible remain unclear. We hypothesized that isoflavones may differ in their cardiac actions in view of their varying affinities for the estrogen receptor and differences in ability to inhibit tyrosine kinase. We investigated the direct effects of three closely related isoflavones, genistein, daidzein, and equol (a metabolite of daidzein formed by gut microflora), on the contractile function of isolated guinea pig ventricular myocytes. Genistein (10 and 40 microM) significantly increased cell shortening and the Ca(2+) transient (measured using indo-1). In contrast, equivalent concentrations of equol produced the opposite effect, decreasing cell shortening and the Ca(2+) transient, whereas daidzein was without effect. The opposing actions of genistein and equol were still observed in the presence of the specific estrogen receptor antagonist ICI 182,780 (10 microM). However, the stimulatory actions of genistein were markedly reduced in the presence of the potent phosphotyrosine phosphatase inhibitor, bpV(phen). Both genistein and equol significantly inhibited the peak L-type Ca(2+) current. We conclude that genistein and equol affect the contractile function of ventricular myocytes in opposing ways despite a common initial action of Ca(2+) current antagonism. These differences occur independently of the estrogen receptor but may be partly related to the unique actions of genistein as a tyrosine kinase inhibitor. Furthermore, isoflavone metabolites, such as equol, may be more biologically active than their precursors and have a greater role in cardioprotection than previously realized.

Animals↗
PubMed2003

A toxicity identification evaluation approach to studying estrogenic substances in hog manure and agricultural runoff.

Spreading liquid manure on agricultural fields is a routine way of disposing of animal manure and optimizing the use of nutrients for crops. Limited studies suggest that these wastes may contain a variety of endocrine-disrupting compounds (EDCs) that may be released into aquatic environments through runoff. The purpose of this study was to apply a toxicity identification and evaluation approach to isolate and identify estrogenic compounds in hog manure. A recombinant yeast estrogen screen bioassay was used to detect estrogenicity of high-performance liquid chromatography--separated hog manure fractions. Further analytical analyses of the fractions and comparison to authentic standards resulted in the identification of the endogenous estrogens 17 beta-estradiol (E2) and estrone, and the phytoestrogen metabolite, equol. High levels of equol (6.9-16.6 ppm) were found to be present in manure that was stored for several months. The endocrine-disrupting potential of equol was characterized further by using fish hormone estrogen receptor (ER), sex hormone binding protein (SSBP), and goldfish androgen receptor (AR) radioligand binding assays. Equol was found to be approximately 1,000- and 200-fold less potent that E2 in competing for binding sites of the SSBP and ER, respectively. Equol's potency was 2,200-fold less than testosterone for the AR. Additional studies confirmed the presence of compounds with estrogenic activity in tile drain water after application of hog manure to an agriculture field. In this case, the contribution of equol to the total estrogenicity of the tile drain water was minimal relative to that of natural estrogens. Overall, this study indicates that further work is warranted to assess the impact that EDCs that originate from agricultural runoff may have on the ecology or physiology of exposed biota.

Agriculture↗
PubMed1995

The effects of phytoestrogens on neonatal rat uterine growth and development.

Phytoestrogens found in clover, alfalfa, and soybeans have caused reproductive toxicity in several mammalian species. Other estrogens, such as diethylstilbestrol (DES), are developmental toxicants, reducing uterine estrogen receptor (ER) concentration, altering uterine growth, and eliciting reproductive tract abnormalities in the rat. The present study examines the effects of the phytoestrogens coumestrol and equol on the developing rat uterus. Various doses of these compounds were injected sc on postnatal days (PND) 1-5 or 1-10 to ascertain their effects on uterine weight and ER levels, and on PND 10-14 to determine their effects on uterine weight and gland genesis. Coumestrol (PND 1-5) was about 10(-3) as potent as DES in increasing uterine weight (wet or dry) while equol increased dry weight only, with a potency of 10(-5) that of DES. Although the 10 and 100 micrograms doses of coumestrol (PND 1-5 or 1-10) initially increased uterine wet weight, by PND 20 uterine weights either equaled or fell significantly below controls. The 100-micrograms dose of coumestrol (PND 1-5 or 1-10) reduced ER levels at all ages, while the 10-micrograms dose was not as effective. Equol (PND 1-5 or 1-10) did not affect ER levels. Premature uterine gland genesis occurred by PND 9 for the PND 1-5 100-micrograms coumestrol dose. When given on PND 10-14 (the critical period of gland genesis), 10 micrograms and 100 micrograms of coumestrol and 10 micrograms DES greatly increased uterine weight, while no effect was elicited by equol. Although coumestrol and equol inhibited uterine gland genesis in a dose-dependent manner, neither abolished gland genesis as did 10 micrograms of DES or tamoxifen. These data demonstrate that coumestrol elicits uterine biochemical and morphological toxicity much like DES. Equol decreased uterine gland number without increasing uterine wet weight or luminal epithelial hypertrophy, which is inconsistent with either an estrogenic or antiestrogenic action in the uterus.

Animals↗
PubMed1999

The effects of phytoestrogens on human pancreatic tumor cells in vitro.

Diet has been implicated as a possible link to the etiology, promotion and/or progression of many diseases, including cancer. Recently, interest has been focused on the cancer-protective role of several of the hormone-like diphenolic phytoestrogens, lignans, and isoflavonoids. This study examined the chemoprotective effects of genistein, biochanin A, equol, and coumestrol on human pancreatic adenocarcinoma cells in vitro. Two human adenocarcinoma cell lines, HPAF-11 from a male and Su 86.86 from a female, were used. HPAF-11 cells were exposed for 24 h to these agents at concentrations of 1 and 10 microM. Su 86.86 cells were exposed for 24 h at a concentration of 1 microM. Coumestrol and equol at higher concentrations were toxic to the Su 86.86 cells. These agents displayed marked differences between cell lines in inhibition of growth. Equol and coumestrol inhibited the growth of the female pancreatic tumor cells by 95%; however, these agents stimulated the growth of pancreatic tumor cells from the male. Genistein also stimulated growth in the male pancreatic tumor cells, but had little effect on pancreatic tumor cells from the female. Biochanin A inhibited growth of both male and female tumor cells, but to a lesser extent than other agents. This study also indicated a difference in K-ras expression in pancreatic tumors cells treated with these agents. Equol and coumestrol decreased K-ras expression in the female tumor cell line. Genistein increased expression of K-ras in both male and female pancreatic tumor cells. Genistein also increased expressions of the multidrug resistant (mdr-1) gene in the male tumor-cell line, while coumestrol and biochanin A decreased expression. Equol had no effect on mdr-1 expression. Whether the chemoprotective potential of equol and coumestrol against pancreatic cancer is greater in females than males is being further studied.

Analysis of Variance↗
PubMed1998

Regulation of c-fos transcription by chemopreventive isoflavonoids and lignans in MDA-MB-468 breast cancer cells.

Isoflavonoids and lignans are diet constituents with chemopreventive properties. We compared the ability of the isoflavonoids genistein and equol, the lignans enterodiol, enterolactone and nordihydroguaiaretic acid (NDGA) and the lignan metabolite methyl p-hydroxyphenyllactate to interfere with mitogenic and tumour promotional signal transduction pathways. Their effects on c-fos mRNA levels after induction by either epidermal growth factor (EGF) or the tumour promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was measured in human breast cancer-derived MDA-MB-468 cells. Of the six agents, only genistein decreased EGF-induced, c-fos transcription (by 63% compared to control at 100 mumol/l). In contrast, both genistein and equol at 100 mumol/l decreased TPA-induced c-fos levels, by 75 and 67%, respectively. NDGA and methyl p-hydroxyphenyllactate did not inhibit TPA mediated c-fos transcription and enterolactone and enterodiol had only a weak inhibitory effect. NDGA at 0.1-10 mumol/l increased c-fos mRNA levels. None of the agents inhibited protein kinase C and only genistein inhibited EGF receptor-linked protein tyrosine kinase obtained from MDA-MB-468 cells, with an IC50 of 60 mumol/l. NDGA and genistein arrested cell colony formation potently, genistein was 15-fold more growth-inhibitory than equol. The results suggest that both genistein and equol interfere similarly with TPA-induced signal transduction pathways. Inhibition by genistein of EGF-induced c-fos mRNA transcription is probably related to its interruption of EGF receptor-linked protein tyrosine kinase, whereas genistein-induced growth arrest is not. If ability to antagonise phorbol ester effects is important for chemopreventive efficacy, equol and genistein might be equi-efficacious chemopreventors, whereas enterolactone, enterodiol and NDGA should be much less potent. If phorbol ester antagonism together with antimitogenic activity determine optimal chemopreventive activity of this type of agent, genistein would be more potent than equol.

Breast Neoplasms↗
PubMed2003

Quantitation of soy-derived phytoestrogens in human breast tissue and biological fluids by high-performance liquid chromatography.

A new and reliable HPLC method for the quantitation of daidzein, equol, and genistein in human breast tissue has been developed. The method was applied to biopsies from women undergoing breast reductions, who, prior to surgery, had ingested either a soy isoflavone preparation or a placebo tablet. The results were compared with data collected for urine and serum of the same subjects using standard methods. The limits of detection in the breast tissue homogenate were 24.7 nmol/l for daidzein, 148.0 nmol/l for equol, and 28.4 nmol/l for genistein (S/N of 3). The chromatographic limits of quantitation were 62.5 nmol/l for daidzein and genistein, and 125.0 nmol/l for equol, for which the accuracies were 86.0%, 83.6%, and 81.8%, respectively. The coefficients of variation of these measurements were all below 20% (11.1% for daidzein, 16.4% for genistein, and 13.2% for equol). The sample preparation comprised a concentration step and the absolute limits of quantitation were, therefore, 4.7 nmol/l, 18.8 nmol/l, and 0.94 nmol/l for daidzein and genistein, and 9.4 nmol/l, 37.5 nmol/l, and 1.9 nmol/l for equol in urine, serum, and breast tissue homogenate, respectively. Recoveries were between 70% (+/-5.6%) in breast tissue homogenate and 100% (+/-14.1%) in urine and serum for all three compounds. Equol (less than 1 micromol/l homogenate) was found to be the predominant phytoestrogen in breast tissue and its concentrations exceeded those in serum. The concentrations of phytoestrogens were at least 100-fold higher in urine than in serum and breast tissue.

Breast↗
PubMed2003

Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response element.

Binding of estrogen receptor (ER) to estrogen response element (ERE) induces gene activation and is an important step in estrogen-induced biological effects. Here, we investigated the effects of some dietary phytoestrogens such as the isoflavones genistein and daidzein, its metabolite equol, and the coumestane coumestrol on the binding rate of ERalpha and ERbeta to ERE by a nonradioactive real-time method, the Biacore Technology. ERalpha and ERbeta were able to bind to ERE immobilized on the surface of a sensor chip even in the absence of estrogens. 17beta-Estradiol and phytoestrogens induced an increase in ER binding to ERE in a concentration-dependent manner. 17beta-Estradiol was a more potent activator of binding than the phytoestrogens studied. The concentrations of 17beta-estradiol inducing an increase in the binding response of ERalpha and ERbeta to ERE by 50% (EC(50)) as compared to unliganded ER were 0.03 and 0.01 microM, respectively. Regarding the efficacy of activation of ERalpha, from the most to the least effective compound, the sequence and the EC(50) were as follows: 17beta-estradiol (0.03 microM) > coumestrol (0.2 microM) > equol (3.5 microM) > genistein (15 microM) > daidzein (>300 microM) and for ERbeta 17beta-estradiol (0.01 microM) > coumestrol (0.025 microM) > genistein (0.03 microM) > daidzein (0.35 microM) > equol (0.4 microM). The ratios EC(50)alpha/EC(50)beta were calculated to be for 17beta-estradiol, 3; coumestrol, 8; equol, 8.8; genistein, 500; daidzein > 850. These ratios indicate that genistein and daidzein preferentially activate the binding of ERbeta to ERE. The endogenous hormone 17beta-estradiol as well as coumestrol and daidzein metabolite equol activate the binding of ERbeta to ERE only slightly more effectively than the binding of ERalpha to ERE. Thus, the effect of daidzein can be changed from a specific activator of ERbeta to an activator of both ER isotypes alpha and beta in humans who are able to convert daidzein to equol. While the results of the measurements with ERalpha were in line with the binding affinities of compounds tested for ER, there was a distinct difference between our results and the binding affinities of phytoestrogens for the ERbeta. This leads to the conclusion that phytoestrogens differ not only in their binding affinities for the ER, but also in their potential to increase the rate of receptor binding to the ERE.

DNA↗
PubMed2004

Plasma phytoestrogens are not altered by probiotic consumption in postmenopausal women with and without a history of breast cancer.

Soy phytoestrogens were suggested to reduce the risk of a number of diseases including breast cancer. Given that these compounds are metabolized by bacteria, alteration of intestinal bacteria and enzymes may affect phytoestrogen metabolism. We hypothesized that probiotics, when consumed with soy protein, would increase plasma isoflavones, as well as equol producer frequency, in postmenopausal women. We further hypothesized that these effects would differ between women who have had breast cancer and women who have not. To test these hypotheses, 20 breast cancer survivors and 20 controls completed four 6-wk treatments in a randomized, crossover design: supplementation with soy protein (S) (26.6 +/- 4.5 g protein, 44.4 +/- 7.5 mg isoflavones/d); soy + probiotics (S+P) (10(9) colony-forming units Lactobacillus acidophilus DDS+1 and Bifidobacterium longum, 15-30 mg fructooligosaccharide/d); milk protein (M) (26.6 +/- 4.5 g protein/d); and milk + probiotics (M+P). Plasma phytoestrogen concentrations did not differ between controls and survivors, although genistein tended to be lower in survivors at baseline (P = 0.15), and during soy (P = 0.16) and milk protein (P = 0.16) consumption. As expected, soy consumption increased plasma phytoestrogen concentrations (P < 0.0001). Plasma phytoestrogen concentrations and the number of equol producers did not differ between the S and S+P diets. At the same time, plasma equol concentrations as well as urinary equol excretion in 2 subjects were more than 7-fold different between the 2 diets. These results indicate that this particular probiotic supplement does not generally affect plasma isoflavones, although the large differences between plasma and urinary equol in some subjects suggest that equol producer status may be modifiable in some individuals.

Biological Availability↗
PubMedDate not supplied

Effect of isolated isoflavone supplementation on ABCA1-dependent cholesterol efflux potential in postmenopausal women.

OBJECTIVE: Isoflavones may display beneficial health effects in postmenopausal women. We studied in a clinical trial whether isolated isoflavone treatment in postmenopausal women could affect reverse cholesterol transport as evaluated by adenosine triphosphate-binding cassette A1- (ABCA1), dependent cholesterol efflux from macrophages. In addition, various serum lipid and lipoprotein parameters were investigated. Furthermore, we separately assessed equol-producing and non-equol-producing women. DESIGN: Postmenopausal women (n=56) were treated with either isoflavone or placebo tablets for 3 months in a crossover design, separated by a 2-month washout period. Fifteen women were classified as equol producers, and 15 women were classified as non-equol producers. Serum samples were collected before and after each treatment period. [H]-Cholesterol-labeled J774 macrophage cells, with and without ABCA1 up-regulation, were incubated with the samples, and ABCA1-dependent cholesterol efflux and serum lipid and lipoprotein levels were assessed. RESULTS: Serum promoted 3.1%+/-1.1% and 3.2%+/-1.1% cholesterol efflux from macrophages after isoflavone and placebo treatment, respectively. Thus, isoflavone supplementation did not affect ABCA1-dependent cholesterol efflux to serum. However, as a novel finding, isoflavone treatment increased a subclass of high-density lipoprotein, the pre-beta high-density lipoprotein levels by 18% without affecting any other serum lipid concentrations. ABCA1-facilitated cholesterol efflux and lipid parameters did not differ between equol-producing and non-equol-producing women. CONCLUSION: In postmenopausal women, isolated isoflavone treatment does not affect ABCA1-dependent cholesterol efflux potential from macrophages but increases circulating pre-beta high-density lipoprotein level, which could provide beneficial vascular effects.

ATP-Binding Cassette Transporters↗
PubMed1991

Phytoestrogens: new ligands for rat and human alpha-fetoprotein.

The binding of the lignans, enterolactone, enterodiol, nordihydroguaiaretic acid (NDGA), and the isoflavonic phytoestrogen equol, to human and rat alpha-fetoprotein (AFP) was studied. They had differential inhibitory effects (NDGA greater than equol greater than enterolactone greater than enterodiol) on the binding of estrone and estradiol to rat AFP and the binding of unsaturated fatty acid to both rat and human AFP. Inhibition was dose-dependent. The apparent dissociation constants (Kd) for phytoestrogens binding to AFP were: Kd NDGA = 5 +/- 1.2.10(-7) M, Kd equol = 6.7 +/- 0.8.10(-6) M, Kd enterolactone = 1.7 +/- 0.4.10(-5) M and Kd enterodiol = 2.2 +/- 0.6.10(-5) M. The Kd for estrone binding to rat AFP was increased by increasing concentrations of equol, but the number of esterone binding sites remained unchanged. This, plus the results of double-reciprocal plots, suggests that they compete for the same site(s). NDGA also competitively inhibited estrone binding at low NDGA concentrations (increased Kd), but high concentrations induced conformational changes in rat AFP, as both Kd and the number of binding sites (n) were altered. Both rat and human AFPs underwent changes in electrophoretic behaviour and loss of immunoreactivity with increasing NDGA, suggesting that NDGA binding induces conformational changes in the AFPs. However, equol did not alter the electrophoretic or immunological properties of either rat or human AFP, providing further evidence for qualitative differences in the effects of these diphenols. These findings indicate that phytoestrogens could play a role in AFP-dependent normal and pathological growth and development.

4-Butyrolactone↗
PubMed2000

Estrogenic activity of flavonoids in mice. The importance of estrogen receptor distribution, metabolism and bioavailability.

The in vivo estrogenic potential of the flavonoids apigenin, kaempferol, genistein and equol was investigated in immature female mice. Genistein and equol, administered by gavage for 4 consecutive days [post-natal day (PND) 17-20, 100 mg/kg body weight], was found to significantly increase uterine weights and the overall uterine concentration of estrogen receptor alpha (ERalpha). In kaempferol- and equol-exposed mice the cytosolic ERalpha concentration was significantly increased as compared to the solvent control, which is speculated to result in an increased sensitivity of the uterus to subsequently encountered estrogens. Oral administration of equol, genistein, biochanin A and daidzein to 6-week-old female mice revealed a great variation in their systemic bioavailability. The urinary recovery of equol was thus over 90% of a single gavage administered dose, whereas the urinary recoveries of biochanin A, genistein and daidzein were 16, 11 and 3%, respectively. Most of the metabolites were either hydroxylated or dehydrogenated forms of the parent compounds. The in vitro estrogenic potency of some of the metabolites was greater than that of the parent compounds, whereas others were of similar or lower potency. Bioavailability, metabolism, the ability to alter ERalpha distribution in the uterus and the estrogenic potential of parent compound and metabolites may thus contribute to the differences in in vivo estrogenicity of dietary flavonoids.

Animals↗