Soy Processing Affects Metabolism and Disposition of Dietary Isoflavones in Ovariectomized Balb/c Mice
ABSTRACT Soy foods and nutritional supplements are widely consumed for potential health benefits. It was previously shown that isoflavone-supplemented diets, which contained equal genistein equivalents, differentially stimulated mammary tumor growth in athymic mice based on the degree of processing. This paper reports plasma pharmacokinetic analysis and metabolite identification using the parental mouse strain fed the same diets, which contained genistin, mixed isoflavones, Novasoy, soy molasses, or soy flour plus mixed isoflavones. Whereas the degree of soy processing did affect several parameters reflecting isoflavone bioavailability and gut microflora metabolism of daidzein to equol, stimulation of tumor growth correlated significantly with only the plasma concentration of aglycon genistein produced by the diets. This conclusion is consistent with the known estrogen agonist activity of genistein aglycon on mammary tumor growth. Conversely, plasma equol concentration was inversely correlated with the degree of soy processing. Although antagonism of genistein-stimulated tumor growth by equol could explain this result, the very low concentration of aglycon equol in plasma (12-fold lower relative to genistein) is inconsistent with any effect. These findings underscore the importance of food processing, which can remove non-nutritive components from soy, on the pharmacokinetics and pharmacodynamics of isoflavones. Such changes in diet composition affect circulating, and presumably target tissue, concentrations of genistein aglycon, which initiates estrogen receptor-mediated processes required for the stimulation of tumor growth in a mouse model for postmenopausal breast cancer.
- SourceAvailable from: Estatira Sepehr
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- "Differences in phase II metabolism between equol and genistein may also contribute to the disparate cognitive outcomes measured between these isoflavones. Research has indicated a significantly lower fraction of bioavailable (aglycone) equol relative to genistein in plasma following dietary isoflavone exposure to mice (Allred et al., 2005), an effect confirmed in our pilot blood level study (see methods). Blood levels achieved by our dosing regimen parallel those occurring in humans after consuming a high dose of S-equol and are about 10-fold greater than serum concentrations in humans after taking a therapeutic dose of 10–20 mg (Jackson et al., 2011; Setchell et al., 2005). "
ABSTRACT: The use of over-the-counter botanical estrogens containing isolated soy isoflavones, including genistein and daidzein, has become a popular alternative to traditional hormone therapies. Menopausal women use these products as an aide in healthy aging, including for the maintenance of cognitive function. The safety and efficacy of many of these commercial preparations remains unknown. Previous research in our lab found that treatment of ovariectomized (OVX) female Long-Evans rats with genistein impaired working memory in an operant delayed spatial alternation (DSA) task and response learning in a plus-maze, but enhanced place learning assessed in the plus-maze. The present study further examined the effects of isolated isoflavones on working memory and place learning by treating middle-aged (12-13month old) OVX female Long-Evans rats with S-equol, the exclusive enantiomer produced by metabolism of daidzein in the mammalian gut. S-equol binds selectively to ERβ with an affinity similar to that of genistein but has low transcriptional potency. For DSA testing, S-equol at 1.94, 0.97mg, or 0mg (sucrose control) was orally administered to animals daily, 30minutes before behavioral testing, and again both 4 and 8hours after the first treatment. Rats were tested on the DSA task following the first, morning dose. For place learning, rats received 0.97mgS-equol every 4hours during the light portion of the cycle beginning 48hours prior to behavioral testing (total exposure 8.7mgS-equol). S-equol treatment was largely without effect on the DSA and place learning tasks. This is the first study to test the behavioral effects of isolated S-equol in OVX rodents, and shows that, unlike genistein or estradiol, repeated daily treatment with this isoflavone metabolite does not alter learning and memory processes in middle-aged OVX rats.Neurotoxicology and Teratology 12/2013; 41. DOI:10.1016/j.ntt.2013.12.004 · 3.22 Impact Factor
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- "With respect to tamoxifen, previous studies provide evidence that tamoxifen induces caspase-dependent apoptosis in MCF-7 and other types of cancer cells [30,32,50-53]. Even though high concentrations of equol (100 μM) were required to activate MCF-7 apoptosis, which are not physiologically achievable in human plasma due to metabolic conversion of the active aglycone equol to the inactive conjugated form , our results may find applications in targeted immunotherapies, which may enable maximal delivery of equol into the cancer cells. This strategy was previously used successfully for genistein, which was immunoconjugated with a monoclonal antibody and targeted to a B cell-specific receptor for treatment of an animal model of B-cell precursor leukemia . "
ABSTRACT: Background Soy phytoestrogens, such as daidzein and its metabolite equol, have been proposed to be responsible for the low breast cancer rate in Asian women. Since the majority of estrogen receptor positive breast cancer patients are treated with tamoxifen, the basic objective of this study is to determine whether equol enhances tamoxifen’s anti-tumor effect, and to identify the molecular mechanisms involved. Methods For this purpose, we examined the individual and combined effects of equol and tamoxifen on the estrogen-dependent MCF-7 breast cancer cells using viability assays, annexin-V/PI staining, cell cycle and western blot analysis. Results We found that equol (>50 μM) and 4-hydroxy-tamoxifen (4-OHT; >100 nM) significantly reduced the MCF-7 cell viability. Furthermore, the combination of equol (100 μM) and 4-OHT (10 μM) induced apoptosis more effectively than each compound alone. Subsequent treatment of MCF-7 cells with the pan-caspase inhibitor Z-VAD-FMK inhibited equol- and 4-OHT-mediated apoptosis, which was accompanied by PARP and α-fodrin cleavage, indicating that apoptosis is mainly caspase-mediated. These compounds also induced a marked reduction in the bcl-2:bax ratio, which was accompanied by caspase-9 and caspase-7 activation and cytochrome-c release to the cytosol. Taken together, these data support the notion that the combination of equol and tamoxifen activates the intrinsic apoptotic pathway more efficiently than each compound alone. Conclusions Consequently, equol may be used therapeutically in combination treatments and clinical studies to enhance tamoxifen’s effect by providing additional protection against estrogen-responsive breast cancers.BMC Cancer 05/2013; 13(1):238. DOI:10.1186/1471-2407-13-238 · 3.32 Impact Factor
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- "Soybean isoflavones represent a class of naturally occurring plant phytochemicals characterized by a steroid-like structure and weak estrogenic activity (Gennari 1999). Their glycosidic bonds may be hydrolyzed by intestinal microflora resulting in the formation of active forms in the serum or urine of animals (Allred et al. 2005; Xu et al. 1995). Several animal studies in intact and ovariectomized mice have provided convincing data on the significant enhancement of bone mass or other biochemical parameters by administration soy isoflavonoids (e.g., genistein, daidzein, or its metabolite , equol) and other phytoestrogens which are summarized in Table 2. To elucidate the possible mechanisms and differences in the mode of action of the various phytoestrogens, we have compared the results obtained in different species of rats and mice. "
ABSTRACT: Phytoestrogens are a class of bioactive compounds derived from plants and exert various estrogenic and antiestrogenic effects. Estrogen deficiency osteoporosis has become a serious problem in elderly women. The use of ovariectomized (OVX) rat or mice models to simulate the postmenopausal condition is well established. This review aimed to clarify the sources, biochemistry, absorption, metabolism, and mode of action of phytoestrogens on bone health in intervention studies. In vitro, phytoestrogens promote protein synthesis, osteoprotegerin/receptor activation of nuclear factor-kappa B ligand ratio, and mineralization by osteoblast-like cells (MC3T3-E1). In the OVX murine model, administration of phytoestrogens can inhibit differentiation and activation of osteoclasts, expression of tartrate-resistant acid phosphatase, and secretion of pyridinoline compound. Phytoestrogens also enhance bone formation and increase bone mineral density and levels of alkaline phosphatase, osteocalcin, osteopontin, and α1(I) collagen. Results of mechanistic studies have indicated that phytoestrogens suppress the rate of bone resorption and enhance the rate of bone formation.Applied Microbiology and Biotechnology 01/2013; 97(4). DOI:10.1007/s00253-012-4675-y · 3.81 Impact Factor