Role of Isoflavones in the Hypocholesterolemic Effect of Soy

Epidemiologic data suggest an inverse relationship between the consumption of soy isoflavones and cardiovascular disease risk. The aims of this review are to determine if isoflavones play a role in the hypocholesterolemic effect of soy and whether the studies realized with that scope were adequately designed. In humans, most studies have been performed in postmenopausal women. The results are inconsistent, however; some studies show a decrease in total cholesterol and low-density lipoprotein concentrations, and an increase in high-density lipoprotein levels, and other investigations fail to show any beneficial effect of soy isoflavones on lipid profiles. In most studies, beneficial effects could not be attributed with certainty to soy isoflavones. If these components have any health-protecting effect in humans, it is small in comparison with the effect of soy protein itself. There are currently not enough data to recommend the consumption of isoflavone supplements to lower plasma cholesterol levels.     

The synthesis of multiply 13C‐labelled plant and mammalian lignans as internal standards for LC‐MS and GC‐MS analysis

The syntheses of multiply ¹³C‐labelled derivatives of the two mammalian lignans, enterolactone and enterodiol, and two of their plant lignan precursors, secoisolariciresinol and matairesinol, are described. Three ¹³C atoms were incorporated into each lignan using potassium [¹³C]cyanide as the source for all of the ¹³C atoms. The compounds were prepared for use as internal standards in the LC‐MS and GC‐MS analysis of lignans. Copyright © 2005 John Wiley & Sons, Ltd.     

基于下丘脑-垂体-卵巢轴探讨藏药二十五味鬼臼丸对绝经后骨质疏松症大鼠的干预作用

目的基于下丘脑-垂体-卵巢轴(hypothalamus-pituitary-ovary axis,HPOA)探讨藏药二十五味鬼臼丸对去卵巢大鼠骨质疏松的影响。方法将40只SD雌性未孕大鼠随机分为假手术组、模型组、雌二醇组、二十五味鬼臼丸组,每组10只。除假手术组仅摘取卵巢旁同样大小的脂肪块,其余3组大鼠均摘除双侧卵巢建立绝经后骨质疏松症(postmenopausal osteoporosis,PMOP)大鼠模型。手术1周后开始给药处理,雌二醇组ig0.1mg/kg戊酸雌二醇,二十五味鬼臼丸组ig441mg/kg二十五味鬼臼丸,假手术组和模型组ig等体积蒸馏水,1次/d,连续12周后,ELISA法检测血清雌二醇、黄体生成素(luteinizing hormone,LH)、卵泡刺激素(follicle stimulating hormone,FSH)、促性腺激素释放激素(gonadotropin releasing hormone,GnRH)水平;RT-PCR检测下丘脑、垂体、左侧股骨远端雌激素受体α(estrogen receptorα,ERα)、雌激素受体β(estrogen receptorβ,ERβ)m RNA表达;免疫荧光染色法检测下丘脑、垂体和右侧股骨远端ERα、ERβ蛋白表达;HE染色法观察大鼠右侧股骨远端组织形态变化;Micro-CT检测右侧股骨远端微结构的改变。结果藏药二十五味鬼臼丸能显著降低大鼠体内血清LH、FSH、GnRH水平(P0.05、0.01),并在HPOA轴中显著性上调下丘脑及垂体ERαm RNA及蛋白表达(P0.01),同时显著性上调股骨ERβm RNA及蛋白表达(P0.01),并能显著回调大鼠股骨密度及骨微结构参数(P0.01)。结论藏药二十五味鬼臼丸可有效防治PMOP,其机制可能与药物直接作用骨组织雌激素受体或作用HPOA轴靶器官相关雌激素受体后,通过改变体内性激素的水平间接调控骨代谢有关。     

湖北海棠总黄酮对卵巢早衰大鼠卵巢功能及骨代谢的影响

目的观察湖北海棠总黄酮对卵巢早衰大鼠卵巢功能及骨代谢的影响。方法将48只成年雌性大鼠随机分为空白组、模型组、戊酸雌二醇组及湖北海棠总黄酮高、中、低剂量组,每组8只。除空白组外,其余各组每天给予灌胃雷公藤多苷片(75 mg/kg),连续14 d,复制卵巢早衰模型。第15天起,戊酸雌二醇组给予灌胃戊酸雌二醇(1 mg/kg);湖北海棠总黄酮高、中、低剂量组分别给予灌胃湖北海棠总黄酮(160、80、40 mg/kg),每日1次,连续给药21 d。观察各组大鼠:动情周期;卵巢指数、子宫指数;血清中雌激素(E2)、孕激素(P)、卵泡刺激素(FSH)、黄体生成素(LH)水平变化;卵巢、子宫形态学变化;血清碱性磷酸酶(ALP)、骨碱性磷酸酶(BALP)活性、1,25(OH)_2D_3含量、超氧化物歧化酶(SOD)活力、丙二醛(MDA)含量,检测卵巢组织中ERα的表达。结果与空白组比较,模型组大鼠动情周期紊乱,卵巢指数、子宫指数降低,血清中E2、P水平降低,FSH水平升高(P0. 05,P0. 01)。与模型组比较,戊酸雌二醇组和湖北海棠总黄酮治疗组血清生殖激素水平得到明显改善(P0. 05),卵巢内生长卵泡数量增多,子宫内膜增厚,血清中ALP活力、BALP含量降低,1,25(OH)_2D_3含量升高(P0. 05,P0. 01);血清中SOD活力增强,MDA含量降低;卵巢组织中颗粒细胞、基质细胞ERα的表达增强。结论湖北海棠总黄酮对卵巢早衰大鼠卵巢及骨质疏松具有一定的治疗保护作用,其作用机制可能与体内抗氧化能力、增强颗粒细胞内雌激素受体的表达密切相关。     

Genistein accumulates in body depots and is mobilized during fasting, reaching estrogenic levels in serum that counter the hormonal actions of estradiol and organochlorines.

Isoflavones are important dietary compounds that are consumed with the daily diet and elicit important biological actions. Here we report on the ability of genistein to partially accumulate in body depots of male mice, be released following fasting, and modulate the actions of estradiol and environmental estrogens in reproductive and nonreproductive target organs of estrogen-reporter mice (ERE-tK-luciferase). After the consumption of 50 mg/kg/day for 3 days, genistein accumulates in body compartments where it remains at functionally active levels for at least 15 days. Following 48 h of fasting, its concentration increased in serum from 99 +/- 13 to 163 +/- 17 nM. These levels are sufficient to exert an estrogenic effect in the testis and liver, as revealed by a twofold increase in luciferase gene expression. beta-Benzene-hexachloride (betaBHC) given at the concentration of 100 mg/kg/day for 3 days also accumulates in the body and is released by fasting, reaching serum levels of 176 +/- 33 nM, upregulating the luciferase gene in the liver and inhibiting its expression in the testis. When genistein was given in combination with betaBHC at doses sufficient to induce accumulation of both in body depots, the genistein mobilized by fasting reversed the action of the mobilized betaBHC in the testis. Acute administration of nutritional doses of genistein inhibited the action of estradiol and reversed the antiestrogenic action of o,p'-DDT: 1,1,1,-trichloro-2(p-chlorophenyl)-2-(o-chlorophenyl)ethane in the liver and the antiestrogenic action of betaBHC in the testis. Genistein had an additive effect with the ER agonist p,p'-DDT: 1,1,1,-trichloro-2,2-bis(p-chlorophenyl)ethane in the liver. The observed effects may be relevant to a protective action of phytoestrogens against estrogen receptor-interacting pollutants as well as the dietary modulation of estradiol action.     

Circulating enterolactone and prostate cancer risk: a Nordic nested case-control study

Enterolactone, a phytoestrogen belonging to the class of lignans, is produced by the intestinal microflora from precursors in plant foods and has been implicated in protection against cancer. We study the effect of enterolactone on the risk of a subsequent diagnosis of prostate cancer. We conducted a longitudinal, nested case-control study by linkage of 3 biobanks to the cancer registries in Finland, Norway and Sweden, respectively. Enterolactone concentrations were measured by time-resolved fluoroimmunoassay in serum from 794 men who had a diagnosis of prostate cancer at a mean follow-up time of 14.2 years after blood collection and among 2,550 control men matched within each cohort for age (+/-2 years), date of blood collection (+/-2 months) and county. The median enterolactone concentrations did not differ between case and control subjects in the full study group (8.4 nmol/L [25th-75th percentile = 4.5-15.0] vs. 8.5 nmol/L [25th-75th percentile = 4.3-15.9]), nor in the national groups. Odds ratios of prostate cancer risk estimated by conditional logistic regression for increasing concentrations of enterolactone in quartiles in the full study group were 1.00 (referent), 1.21 (95% confidence interval [CI] = 0.96-1.52), 1.16 (95% CI = 0.91-1.47) and 1.08 (95% CI = 0.83-1.39). The OR estimate for the highest vs. the lowest quartile of enterolactone in separate analyses of the Norwegian, Finnish and Swedish cohort was 1.21 (95% CI = 0.91-1.60), 1.02 (95% CI = 0.59-1.76) and 0.87 (95% CI = 0.45-1.67), respectively. No support for the hypothesis that high circulating enterolactone is protective against prostate cancer was found.     

Steroid hormone activity of flavonoids and related compounds

Soy isoflavones have been studied extensively for estrogenic and antiestrogenic properties. Other flavonoids, found in fruits, vegetables, tea and wine, have been much less tested for steroid hormone activity. We therefore assessed the estrogenic, androgenic and progestational activities of 72 flavonoids and structurally-related compounds. These compounds were tested on BT-474 human breast cancer cells at concentrations of 10⁸–10^–5M, with estradiol (estrogen), norgestrel (progestin) and dihydrotestosterone (androgen) used as positive controls, and ethanol (solvent) as a negative control. pS2, an estrogen-regulated protein, and prostate-specific antigen (PSA), regulated by androgens and progestins, were quantified in tissue culture supernatants using ELISA-type immunofluorometric assays developed in-house. Of the 72 compounds tested, 18 showed estrogenic activity at 10^–5M. Of this subset, seven also showed progestational activity at this concentration. The soy isoflavones, biochanin A and genistein, showed the most potent estrogenic activity, with a dose-response effect up to 10^–7 M. Of all other flavonoids, luteolin and naringenin displayed the strongest estrogenicity, while apigenin had a relatively strong progestational activity. Based on our data, we have formulated a set of structure/function relationships between the tested compounds. Flavonoids, therefore, exhibit significant steroid hormone activity, and may have an effect in the modification of cancer risk by diet, or in cancer therapeutics and prevention.     

Sources of Phytoestrogen Exposure among Non-Asian Women in California, USA

Objective: We recently described the development of a comprehensive database for assessing phytoestrogen exposure in epidemiologic studies [1]. This paper describes the first application of this database and the primary sources of phytoestrogen consumption in non-Asian women. Methods: Four hundred and forty-seven randomly selected African-American, Latina, and white women, ages 50 79 years, residing in California's San Francisco Bay Area and participating as controls in an ongoing population-based case-control study of breast cancer, were included in the present analysis. Average daily consumption of each of seven phytoestrogenic compounds was determined for each woman by combining the values from the new database with food consumption reported on a food-frequency questionnaire. Results: Phytoestrogens in the non-Asian Bay Area diet appear to come primarily from: (1) traditional soy-based foods (e.g. tofu and soy milk); (2) "hidden" sources of soy (e.g. foods containing added soy protein is concentrate, or soy flour, e.g. many brands of doughnuts and white bread); and (3) a variety of foods which contain only low to moderate amounts of phytoestrogens per 100 grams but which are frequently consumed (e.g. coffee and orange juice). Conclusions: In the absence of a comprehensive assessment of various phytoestrogens in a wide variety of foods, epidemiologic studies could suffer from the effects of uncontrolled confounding by unmeasured sources of phytoestrogen exposure potentially leading to biased estimates of effect and misinterpretation of findings.     

The effect of two dietary and a synthetic phytoestrogen on transepithelial calcium transport in human intestinal-like Caco-2 cells

Summary Background Recently, dietary phytoestrogens (PEs) have been suggested as possible alternatives to estrogen therapy, as a means of preventing bone loss associated with ovarian hormone deficiency. PEs are non-steroidal, plant-derived compounds that exhibit some estrogen-like activity in some tissues, and which appear to prevent postmenopausal bone loss. While PEs act directly on bone cells, their protective effect on bone may be partly due to their ability to enhance Ca absorption. Aim of the study Therefore, the aim of this study was to investigate the effect of two dietary PEs (coumestrol and apigenin) as well as a synthetic PE, ipriflavone, on Ca absorption in human Caco-2 intestinal-like cells. Methods Caco-2 cells were seeded onto permeable filter supports and allowed to differentiate into monolayers. On d 21, the Caco-2 monolayers (n 10–16 per treatment), grown in estrogen-free or low-estrogen media, were then exposed to 10 nM-1,25 (OH)₂ D₃, or 50 µM ipriflavone, -coumestrol or -apigenin for 48 hours. After exposure, transepithelial and transcellular transport of ⁴⁵Ca and fluorescein transport (a marker of paracellular diffusion) were measured. Results As expected, 1,25 (OH)₂ D₃ stimulated Ca absorption. Treatment with coumestrol or apigenin had no effect on Ca transport. On the other hand, ipriflavone increased total Ca transport (by about 1.5-fold, P < 0.05) under lowestrogen conditions, but not under estrogen-free conditions. This increase in total Ca transport by ipriflavone was via an increased transcellular Ca transport (by about 2-fold, P < 0.05) relative to control. Conclusion In conclusion, the protective effect of dietary PE on bone mass would appear to be due to their direct effect(s) on bone cells, as opposed to an indirect effect on bone by stimulation of intestinal Ca absorption.     

Dietary lignan intakes and risk of pre- and postmenopausal breast cancer

Lignans are plant compounds metabolized in the mammalian gut to produce the phytoestrogens enterolactone and enterodiol. Because estrogens have been linked to breast cancer etiology, lignans could affect breast cancer risk through modulation of endogenous estrogen metabolism or competitive inhibition with estrogen receptors. We examined breast cancer risk and dietary lignan intake in a population-based case-control study of 1,122 women with primary, incident, histologically confirmed breast cancer and 2,036 controls frequency matched to cases on age and county of residence as part of the Western New York Exposures and Breast Cancer (WEB) Study. Diet was assessed with a self-administered 104-item food frequency questionnaire and other relevant data were collected by detailed in-person interviews. Lignans were expressed as the sum of the dietary precursors secoisolariciresinol and matairesinol. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression, adjusting for age, total energy and other breast cancer risk factors. Premenopausal women in the highest quartile of dietary lignan intake had reduced breast cancer risk (OR = 0.66; 95% CI = 0.44-0.98). No association was observed between lignan intakes and postmenopausal breast cancer. Our results suggest that dietary lignans may be important in the etiology of breast cancer, particularly among premenopausal women.