Short-term variations in enterolactone in serum, 24-hour urine, and spot urine and relationship with enterolactone concentrations.
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4-Butyrolactone↗
Biomedical subjects
Herman Adlercreutz
Publications and source records attributed to Herman Adlercreutz.
Serum enterolactone concentration is not associated with prostate cancer risk in a nested case-control study.
The lignan enterolactone, produced by the intestinal microflora from dietary precursors, has been hypothesized to protect against hormone-dependent cancers and cardiovascular diseases. We conducted a nested case-control study to examine the relationship between serum enterolactone concentration and prostate cancer. Enterolactone concentrations were measured by time-resolved fluoroimmunoassay in serum collected at baseline in the alpha-Tocopherol, beta-Carotene Cancer Prevention Study from 214 men with prostate cancer diagnosed during a 6-year follow-up and from 214 controls matched by age, date of baseline blood collection, intervention group, and local study area. Mean serum enterolactone concentration (in nmol/liter) did not differ significantly between case and control subjects [15.9 (SD, 15.2) versus 16.9 (SD, 14.9), respectively (P = 0.42)]. Odds ratios for prostate cancer risk estimated by conditional logistic regression for increasing quartiles of enterolactone concentration were 1.00 (referent), 0.72 [95% confidence interval (CI), 0.43-1.23], 0.98 (95% CI, 0.58-1.68), and 0.71 (95% CI, 0.42-1.21). Our findings do not support the hypothesis that enterolactone is involved in the development of prostate cancer.
4-Butyrolactone↗
Lipoprotein response to diets high in soy or animal protein with and without isoflavones in moderately hypercholesterolemic subjects.
OBJECTIVE: The objective of this study was to assess the independent effect of soy relative to common sources of animal protein and soy-derived isoflavones on blood lipids. METHODS AND RESULTS: Forty-two subjects with LDL cholesterol levels > or =3.36 mmol/L were fed each of four diets in randomized order for 6 weeks per phase. Diets contained a minimum of 25 g animal protein or isolated soy protein/4.2 MJ, with each containing trace amounts or 50 mg of isoflavones/4.2 MJ. Soy protein had a modest effect on total, LDL and HDL cholesterol, and triglyceride concentrations (-2%, P=0.017; -2%, P=0.042; +3%; P=0.034, -11%, P<0.001, respectively). Soy protein had no significant effect on plasma lipids in individuals with LDL cholesterol <4.14 mmol/L and significantly reduced total and LDL cholesterol and triglyceride concentrations in individuals with LDL cholesterol > or =4.14 mmol/L (-4%, P=0.001; -5%, P=0.003; -15%, P<0.001, respectively). No significant effect of isoflavones on plasma lipid levels was observed either constituent to the soy protein or supplemental to the animal protein. CONCLUSIONS: Although potentially helpful when used to displace products containing animal fat from the diet, the regular intake of relatively high levels of soy protein (>50 g/day) had only a modest effect on blood cholesterol levels and only in subjects with elevated LDL cholesterol levels (> or =4.14 mmol/L). Soy-derived isoflavones had no significant effect.
Animals↗
Mammalian lignan formation in rats fed a wheat bran diet.
The dietary origin of lignan phytoestrogens is still poorly understood more than 20 years after their discovery in human urine. Their level in urine has been associated with the consumption of dietary fiber. This paper reports the study of the excretion of enterolactone, assayed by a time-resolved fluoroimmunoassay, in rats fed a diet supplemented with 15% wheat bran, one of the main sources of fiber in Western countries. Enterolactone excretion regularly increased during the two weeks of the diet to reach a value of 45 nmol/day. The level of excretion also increased upon preadaptation to ferulic acid, structurally related to secoisolariciresinol, an established precursor of enterolactone in flaxseeds, and decreased upon preadaptation to potato starch rich in fiber. These results show that the formation of lignans from wheat bran is influenced by the diet, possibly because of an adaptation of the colonic microflora.
4-Butyrolactone↗
Isoflavonoids inhibit catabolism of vitamin D in prostate cancer cells.
The high ingestion of soybean products in Asian countries has been suggested to be responsible for a reduced incidence of prostate cancer. The mechanism of action, however, is unknown. Our data demonstrate that genistein and some isoflavone metabolites reduce the activity of 25-D3-24-hydroxylase (CYP24) in the human prostate cancer-derived cell line DU-145. CYP24 is also responsible for degradation of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 which is known to be antimitotic and prodifferentiating in prostate cancer cells. High levels of CYP24 frequently found in prostate cancer cells may thus degrade the active metabolite. This could be prevented by ingestion of genistein-containing food such as soybeans.
Base Sequence↗
Gas chromatographic-mass spectrometric method for the determination of alkylresorcinols in human plasma.
Alkylresorcinols can be found in high amounts in whole grain cereals, especially in rye. Previously it has not been possible to measure alkylresorcinols in plasma. In this paper a validated gas chromatographic-mass spectrometric method for the quantitative determination of alkylresorcinols with chain lengths of C15:0, C17:0, C19:0, C21:0, and C23:0 in human plasma samples is presented. Other alkylresorcinols may be measured with the method as well, but their assay was not validated in this work. In this work also the amount of alkylresorcinol C25:0 was measured. The pretreatment of plasma samples consists of a simple incubation, an extraction with diethyl ether and a chromatographic purification before the GC-MS analysis. As internal standard an alkylresorcinol C20:0 was used. The validation of the method showed that it fulfilled the reliability criteria. Calibration graphs were linear over the range of 4.1-660pg per injection. The mean recovery percentage was 112+/-10.8%. Our results show that the alkylresorcinols are found in plasma in the same ratio, as found in rye grains, according to literature. The alkylresorcinols were in the unconjugated form. The total amounts of alkylresorcinols in two plasma samples analyzed here were 333 and 381nmol/L.
Alkylation↗
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.
4-Butyrolactone↗
Use of oral antimicrobials decreases serum enterolactone concentration.
The lignan enterolactone, a phytoestrogen, may protect against hormone-dependent cancers and cardiovascular diseases. It is produced by the intestinal microflora from dietary precursors. Because of the pronounced impact of antimicrobials on the intestinal microflora, the authors examined whether serum enterolactone concentration is affected by previous use of oral antimicrobials. Enterolactone was measured by time-resolved fluoroimmunoassay in 2,753 Finnish men and women aged 25--64 years who participated in a cross-sectional national survey in 1997. Background information was collected by self-administered questionnaire, and data on antimicrobial treatment were gathered from the nationwide prescription database of the Social Insurance Institution. Serum enterolactone concentration was significantly lower in those who had used oral antimicrobials up to 12--16 months before serum sampling than in nonusers (16.4 vs. 19.3 nmol/liter). The concentration was associated with the number of treatments and the time from the last treatment. Modest differences were present between various antimicrobials. The authors' findings support the crucial role of gut microflora in the metabolism of lignans. Furthermore, recent use of antimicrobials should be considered when the association between serum enterolactone concentration and risk of chronic diseases is studied.
4-Butyrolactone↗
An incident case-referent study on plasma enterolactone and breast cancer risk.
OBJECTIVE: Using a nested case-referent design, we evaluated the relationship between plasma levels of the lignan enterolactone and the risk of developing breast cancer. METHODS: 248 cases and 492 referents were selected from three population-based cohorts in northern Sweden. Blood samples were donated at enrollment. All blood samples were stored at -80 degrees C. Cases and referents were matched for age, date of blood sample and sampling centre. Breast cancer cases were identified through the regional and national cancer registries. RESULTS: Plasma enterolactone was lower among smokers in all cohorts and in subjects with BMI < 23 and BMI > 28 in one of the cohorts. Low plasma concentrations of enterolactone, below the 12.5(th) percentile (mean plasma enterolactone 2.9 nmol/l), were associated with an increased risk of breast cancer. Also, high values of plasma enterolactone, above the 87.5(th) percentile (mean plasma enterolactone 58.2 nmol/l) were significantly associated with an increased breast cancer risk among women from two cohorts with only incident cases and a higher number of pre-menopausal women. High plasma enterolactone concentrations among older women from a mammary screening project with mostly prevalent cases were associated with a non-significant slightly reduced breast cancer risk. CONCLUSION: Very low plasma concentrations of enterolactone were associated with an increased breast cancer risk in all three cohorts. In two of the cohorts, with only incident cases, very high plasma concentrations were also associated with an increased breast cancer risk. In the third cohort with mainly screen-detected cases from a mammary screening program, high plasma enterolactone concentrations were associated with a weak decreased breast cancer risk.
4-Butyrolactone↗
Association between low serum enterolactone and increased plasma F2-isoprostanes, a measure of lipid peroxidation.
Evidence suggests that low serum enterolactone concentration might be an independent risk factor for acute coronary events. Enterolactone is a lignan, which is formed by intestinal bacteria from precursors in plant foods. Due to the biphenolic structure of enterolactone, it could act as an antioxidant and through this contribute to cardiovascular health. The aim of this study was to test the hypothesis that a low serum enterolactone concentration is associated with increased in vivo lipid peroxidation, assessed by plasma F2-isoprostane concentrations. We investigated this association in a subset of participants in 'The Antioxidant Supplementation in Atherosclerosis Prevention' (ASAP) study. Out of 256 male participants a subsample of 100 consecutive men from baseline was selected for F2-isoprostane assays. The mean serum enterolactone concentration was 16.6 nmol/l and that of F2-isoprostanes 29.6 ng/l. The correlation coefficient for association between serum enterolactone and F2-isoprostane concentrations was -0.30 (P<0.003). Plasma F2-isoprostane levels decreased linearly across quintiles of serum enterolactone concentration (P=0.008 for a linear trend). In a multivariate model, enterolactone persisted as a significant predictor after adjustment for vitamins and other variables, with the strongest associations with F2-isoprostanes. Our present data suggest that low serum enterolactone concentration is associated with enhanced in vivo lipid peroxidation in men.
4-Butyrolactone↗
Time-resolved fluoroimmunoassay of plasma and urine O-desmethylangolensin.
We present a method for the determination of the phytoestrogen metabolite O-desmethylangolensin (O-DMA) in plasma (serum) and in urine. O-DMA is a metabolite of daidzein, which occurs in soybeans. It has been suggested that isoflavones may afford protection against breast and prostate cancer and therefore, also the metabolites are of interest. The method is based on time-resolved fluoroimmunoassay (TR-FIA) using a europium chelate as a label. After the synthesis of 4"-O-carboxymethyl-O-DMA, this compound is coupled to bovine serum albumin, and then used as antigen in immunization of rabbits. The tracers with the europium chelate are synthesized using the same 4"-O-derivative of the alpha-methyldeoxybenzoin. After enzymatic hydrolysis and ether extraction the immunoassay is carried out by time resolved fluoroimmunoassay (TR-FIA). Cross-reactivity was tested with angolensin, dihydrogenistein, dihydrodaidzein, equol, 6'-OH-angolensin, trans-4-OH-equol, 6'-OH-O-DMA, cis-4-OH-equol and 5-OH-equol. The antiserum cross-reacted only with angolensin. This cross-reactivity seems not to influence the results, which were highly specific. Plasma samples are hydrolyzed and extracted. Urine samples are analyzed directly after hydrolysis without extraction. The correlation coefficient between the plasma TR-FIA results and the GC-MS results was high; r value was 0.985. The correlation coefficient between the urine TR-FIA results and the GC-MS results was high over the entire range of concentrations (0-1500 nmol/l); r value was 0.976, but lower in the low concentration range (0-100 nmol/l), i.e. value was 0.631. The intra-assay coefficients of variation (CVs) for plasma O-DMA concentrations and for urine O-DMA concentrations at three different concentrations varied 2.8-7.7 and 3.0-6.0%, respectively and the inter-assay CVs varied 3.8-8.9 and 4.4-6.6%, respectively. The working range of the plasma and urine O-DMA assays was 0.5-512 nmol/l.
Animals↗
Phytoestrogens and breast cancer.
The role of phytoestrogens and consumption of phytoestrogen-rich foods such as soy containing isoflavones and whole grain products with lignans for the prevention of breast cancer is reviewed. It is concluded that soy-containing diet in adult women is not or only slightly protective with regard to breast cancer, but that it may be beneficial if consumed in early life before puberty or during adolescence supporting results of immigrant and epidemiological studies. No negative effects of soy on breast cancer have been observed. On the other hand, a diet low in lignans, resulting in a low plasma enterolactone concentration, increases risk both in a case-control and a prospective study, but some controversial results have also been obtained. Some of these results may be explained by the fact that the determinants of plasma or urinary enterolactone concentration are very different in different countries. In Scandinavia, the main determinants are whole grain cereal food, vegetables and berries. Whether the protective effect is caused by the phytoestrogens in the diet or whether they are only biomarkers of a healthy diet has not been established.
Animals↗
Phyto-oestrogens and cancer.
Phyto-oestrogens have been suggested to have a preventive effect against various cancers. This review includes a discussion of the consumption of phyto-oestrogen-rich foods such as soy, a source of isoflavones, and whole grain products, which contain lignans, and their role in the prevention of breast, prostate, and colon cancer. In women, a soy-containing diet is only slightly protective against breast cancer, if at all, but is more likely to be beneficial if initiated before puberty or during adolescence. These findings are supported by conclusions of studies of immigrants and other epidemiological studies. However, in one case-control study and one prospective study, a low-lignan diet increased the risk of breast cancer. Experimental evidence also exists for an inhibitory effect of soy and rye bran on prostate-cancer growth and for rye bran or isolated lignans on colon cancer. Whether these observed protective effects are caused by the presence of dietary phyto-oestrogens, or whether they are merely indicators of a healthy diet in general, has not been established.
4-Butyrolactone↗
Whole grain food intake elevates serum enterolactone.
Both intake of whole grain and higher levels of serum enterolactone have been related to reduced risk for CHD and some cancers. Because lignans are prevalent in the outer layers of grains, these findings may be related. We carried out a crossover feeding study in which overweight, hyperinsulinaemic, non-diabetic men (n 5) and women (n 6) ate, in random order, wholegrain foods or refined-grain foods in a diet with 30 % energy from fat. The dominant whole grain was wheat, followed by oats and rice. All food was supplied by the investigators and each diet lasted for 6 weeks, with an intervening washout period of 6-9 weeks. Serum enterolactone concentrations were higher when eating the wholegrain than the refined-grain diet by 6.2 (within person SE 1.7) nmol/l (P=0.0008). Most of the increase in serum enterolactone when eating the wholegrain diet occurred within 2 weeks, though the serum enterolactone difference between wholegrain and refined-grain diets continued to increase through 6 weeks. Serum enterolactone concentrations can be raised by eating a diet rich in whole grains.
4-Butyrolactone↗
Phytoestrogens regulate vitamin D metabolism in the mouse colon: relevance for colon tumor prevention and therapy.
Soybean products are highly represented in the traditional Asian diet. Major components of soy proteins are phytoestrogens, such as isoflavones. They may be responsible for the extremely low incidence of prostate and mammary tumors and possibly also of colon cancer in countries such as China and Japan. Serum 1,25-dihydroxyvitamin D3 level is inversely related to incidence of some cancers. Levels are determined by skin exposure to ultraviolet light or, to a minor extent, nutritional uptake and by subsequent conversion of the precursor vitamin D to the active hormone by the cytochrome P450 hydroxylases CYP27A1, CYP27B1 (responsible for synthesis) and CYP24 (responsible for catabolism) in liver and kidney. However, vitamin D synthesis is also found in colonocytes and is enhanced during incipient malignancy. This may indicate an autocrine/paracrine role for this differentiation-inducing hormone in defense against progression. We were able to demonstrate that either a single large oral dose of genistein or feeding soy protein for 4 mo elevated CYP27B1 and decreased CYP24 expression in the mouse colon. Our data therefore suggest that an inverse correlation of soy product consumption with colon tumor incidence may be consequent to enhanced colonic synthesis of the antimitotic hormone 1,25-dihydroxyvitamin D3.
25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
A combination of dietary fructooligosaccharides and isoflavone conjugates increases femoral bone mineral density and equol production in ovariectomized mice.
Fructooligosaccharides (FOS) stimulate the growth of bifidobacteria, which cleave isoflavone conjugates to yield the corresponding aglycones and metabolites. In a previous study, FOS modified the absorption and enterohepatic recirculation of isoflavones in rats. In the present study, we determined the effect of the combination of dietary FOS and isoflavone conjugates on bone mass in ovariectomized (OVX) and surgical control mice. After undergoing OVX or sham operation, female ddY mice (8 wk old, n = 64) were randomly assigned to four groups: a purified control diet (AIN-93G) group, a FOS diet (AIN-93G + 5% FOS) group, an isoflavone diet (AIN-93G + 0.2% isoflavone conjugates) group, or a FOS and isoflavone diet (AIN-93G + 5% FOS + 0.2% isoflavone conjugates) group. After 6 wk, the mice were killed and the blood and femora were sampled immediately. In OVX mice, both isoflavone conjugates and FOS prevented femoral bone loss. An additive effect of dietary isoflavone conjugates and FOS was observed by dual-energy X-ray absorptiometry in the distal part of the femur and in trabecular bone, by peripheral quantitative computed tomography. Moreover, FOS increased cecal beta-glucosidase activity and equol production from daidzein in both OVX and surgical control mice fed isoflavone conjugates. These results suggest that FOS increase the bioavailability of isoflavones, leading to cooperative effects in the prevention of osteopenia in OVX mice.
Absorptiometry, Photon↗
Neurobehavioral effects of dietary soy phytoestrogens.
Phytoestrogens, plant-derived nonsteroidal estrogens found in high abundance in most soy food products, have been studied for their potential beneficial effects against hormone-dependent cancers and age-related diseases. However, little is known about the influence of phytoestrogens on the brain or behavior. This brief review describes mainly our own studies in rodents that have examined the influence of dietary soy isoflavones on certain aspects of brain structure, learning, memory and anxiety along with the brain androgen-metabolizing enzyme, aromatase. These studies used a commercially available diet rich in phytoestrogens (Phyto-rich) vs. a custom diet relatively free of phytoestrogens (Phyto-free). The phytoestrogen content of each diet was determined by high-performance liquid chromatography analysis, circulating plasma phytoestrogen levels were quantified by gas chromatography mass spectroscopy and concentrations of phytoestrogens in specific brain regions were measured by time-resolved fluoroimmunoassay (TR-FIA). Our studies showed that brain aromatase levels were not significantly altered by phytoestrogen diet treatments in perinatal, maternal or adult rats. However, volumes of the sexually dimorphic nucleus of the preoptic area (SDN-POA) were significantly affected by the Phyto-free diet treatment in male rats during adulthood, where SDN-POA volumes were smaller compared to Phyto-rich male values. Additionally, the Phyto-rich diet fed to adult male and female rats produced anxiolytic effects as assessed in the elevated plus maze vs. Phyto-free fed animals. Finally, when learning and memory parameters were examined in a radial arm maze testing visual-spatial memory (VSM), the diet treatments significantly changed the typical sexually dimorphic pattern of VSM. Specifically, adult Phyto-rich fed females outperformed Phyto-free fed females, while in males on the same diets, the opposite pattern of maze performance was observed. When female vs. male performance was compared, Phyto-rich females executed the VSM task in a manner similar to that of Phyto-free fed males, while Phyto-free fed female's VSM was comparable to Phyto-rich males. These results indicate that consumption of dietary phytoestrogens resulting in very high plasma isoflavone levels (in many cases over a relatively short interval of consumption in adulthood) can significantly alter sexually dimorphic brain regions, anxiety, learning and memory. The findings of these studies identify the biological actions of phytoestrogens, specifically isoflavones and their metabolites, found in animal soy-containing diets on brain and behavior and implicate the importance of phytoestrogens given the recognized significance of estrogens in brain and neural disorders, such as Alzheimer's disease, especially in women.
Animals↗
Genistein and 17beta-estradiol, but not equol, regulate vitamin D synthesis in human colon and breast cancer cells.
Extrarenal synthesis of the active vitamin D metabolite 1,25-dihydroxyvitamin-D3 (1,25-D) has been observed in cells derived from human organs prone to sporadic cancer incidence. Enhancement of the synthesizing hydroxylase CYP27B1 and reduction of the catabolic CYP24 could support local accumulation of the antimitotic steroid, thus preventing formation of tumors of e.g., colon and breast. By applying quantitative RT-PCR and HPLC it was observed that in colon-(Caco-2) and breast-(MCF-7) derived cells, 17beta-estradiol and genistein induced CYP27B1 but reduced CYP24 activity, while equol was inactive. Mammary cells express both estrogen receptors (ER) a and beta, while colon cells express mainly ERbeta, possibly explaining why MCF-7 cells were more affected. These results indicate a potential, new approach for cancer prevention by counteraction of the 1,25-D-driven negative feedback, i.e., down-regulation of CYP27B1 and up-regulation of CYP24, which prevents its own local accumulation. However, mammary cells may be more susceptible to this than colonocytes.
25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗