Metabolic Phenotype of Isoflavones Differ among Female Rats, Pigs, Monkeys, and Women
TL;DR: There were significant interspecies differences in isoflavone metabolism, and the overall metabolic profile of pigs was closer to that of women than that of rats or monkeys.
Abstract: Various physiologic effects of soy food consumption have been attributed to the estrogenic actions of isoflavones. The order of estrogen receptor binding potency of soy-derived isoflavone aglycones is equol > genistein > daidzein, and their conjugates are less potent. Because the metabolic profile may be an important determinant of bioactivity after soy intake, we studied the serum and urine isoflavone concentrations in 3 animal models and compared them with isoflavone profiles in women. Female Sprague-Dawley rats, Hampshire/Duroc Cross pigs, cynomolgus monkeys, and women were fed diets containing soy protein isolate. Isoflavones and their metabolites were measured by LC-MS or electrochemical detection. Equol represented approximately 77 and 52% (molar ratio) of summed serum isoflavones (isoflavones plus metabolites) in rats and cynomolgus monkeys, respectively. Equol was undetectable in pig serum and human plasma, but daidzein and genistein contributed >88% of summed circulating isoflavones. Monkey and rat urine contained high levels of aglycones (>85% and >32%, respectively), whereas pigs and women excreted isoflavone mainly in the form of glucuronides (>80%), with <10% as aglycones. Isoflavones in human plasma were predominantly glucuronides (75%) with 24% as sulfates and <1% as aglycones; in monkey serum, however, 64% of isoflavones were sulfates, 30% glucuronides, and 6% aglycones. Equol was also a major serum metabolite of 6-mo-old rhesus monkeys (80% of summed isoflavones). Thus, there were significant interspecies differences in isoflavone metabolism, and the overall metabolic profile of pigs was closer to that of women than that of rats or monkeys.
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TL;DR: The history, chemistry, and factors governing the intestinal bacterial formation of equol, a metabolite of the soy isoflavones, are described and the wide range of biological activities these enantiomers possess warrants their investigation for the treatment of a number of hormone-related conditions involving estrogen-dependent and androgen- related conditions.
Abstract: Equol, first isolated from equine urine in 1932 and identified 50 years later in human urine as a metabolite of the soy isoflavones, daidzin and daidzein, is produced by intestinal bacteria in some, but not all, adults. This observation led to the term equol-producers to define those adults that could make equol in response to consuming soy isoflavones and the hypothesis that the health benefits of soy-based diets may be greater in equol-producers than in equol nonproducers. By virtue of a chiral center, equol occurs as a diastereoisomer and intestinal bacteria are enantiospecific in synthesizing exclusively the S-(-)equol enantiomer, an enantiomer that has selective affinity for the estrogen receptor-β. Both enantiomers are of interest from a clinical and pharmacological perspective and are currently being developed as nutraceutical and pharmacological agents. The wide range of biological activities these enantiomers possess warrants their investigation for the treatment of a number of hormone-related conditions involving estrogen-dependent and androgen-related conditions. The following review describes the history, chemistry, and factors governing the intestinal bacterial formation of equol.
402 citations
TL;DR: The primary research recommendation is that the impact of isoflavones on breast tissue needs to be evaluated at the cellular level in women at high risk for breast cancer.
Abstract: The impact of soyfood intake on breast cancer risk has been investigated extensively. Much of this focus can be attributed to the soybean being a dietary source that is uniquely rich in isoflavones. The chemical structure of isoflavones is similar to that of estrogen, and isoflavones bind to both estrogen receptors (ER alpha and ER beta) (although they preferentially bind to and activate ER beta) and exert estrogen-like effects under some experimental conditions. Isoflavones also possess nonhormonal properties that are associated with the inhibition of cancer cell growth. Thus, there are several possible mechanisms by which soy may reduce the risk of breast cancer. However, the role of isoflavones in breast cancer has become controversial because, in contrast to the possible beneficial effects, some data from in vitro and animal studies suggest that isoflavones, especially genistein, the aglycone of the main soybean isoflavone genistin, may stimulate the growth of estrogen-sensitive tumors. Limited human data directly address the tumor-promoting effects of isoflavones and soy. Because the use of soyfoods and isoflavone supplements is increasing, it is important from a public health perspective to understand the impact of these products on breast cancer risk in women at high risk of the disease and on the survival of breast cancer patients. To this end, a workshop was held in November 2005 to review the existing literature and to make research recommendations. This paper summarizes the workshop findings and recommendations. The primary research recommendation is that the impact of isoflavones on breast tissue needs to be evaluated at the cellular level in women at high risk for breast cancer.
306 citations
TL;DR: Current researches are aimed at identifying the specific bacterial species and strains that are capable of converting daidzein to equol or increasing equol production, which may enhance the actions of soy isoflavones.
Abstract: Soy isoflavones have received considerable attention. Individuals with isoflavones-rich diets have significantly lower occurrences of cardiovascular disease, osteoporosis, and some cancers. The clinical effectiveness of soy isoflavones may be a function of the ability to biotransform soy isoflavones to the more potent estrogenic metabolite, equol, which may enhance the actions of soy isoflavones, owing to its greater affinity for estrogen receptors, unique antiandrogenic properties, and superior antioxidant activity. However, not all individuals consuming daidzein produce equol. Only approximately one-third to one-half of the population is able to metabolize daidzein to equol. This high variability in equol production is presumably attributable to interindividual differences in the composition of the intestinal microflora, which may play an important role in the mechanisms of action of isoflavones. But, the specific bacterial species in the colon involved in the production of equol are yet to be discovered. Therefore, future researches are aimed at identifying the specific bacterial species and strains that are capable of converting daidzein to equol or increasing equol production.
293 citations
Cites background or result from "Metabolic Phenotype of Isoflavones ..."
...For example, equol represents about 77, 52, and 80% of total serum isoflavones in rats, cynomolgus monkeys, and 6-month-old rhesus monkeys, respectively [31]....
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...[31] studied the serum and urine isoflavone concentrations in three animal models and compared them with isoflavone profiles in women....
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...Isoflavones in human plasma were predominantly glucuronides (75%) with 24% as sulfates and <1% as aglycones [31]....
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TL;DR: This review covers each of the major research areas involving soy focusing primarily on the clinical and epidemiologic research, and supports the safety and benefits of soyfoods.
Abstract: Soyfoods have long been recognized as sources of high-quality protein and healthful fat, but over the past 25 years these foods have been rigorously investigated for their role in chronic disease prevention and treatment. There is evidence, for example, that they reduce risk of coronary heart disease and breast and prostate cancer. In addition, soy alleviates hot flashes and may favorably affect renal function, alleviate depressive symptoms and improve skin health. Much of the focus on soyfoods is because they are uniquely-rich sources of isoflavones. Isoflavones are classified as both phytoestrogens and selective estrogen receptor modulators. Despite the many proposed benefits, the presence of isoflavones has led to concerns that soy may exert untoward effects in some individuals. However, these concerns are based primarily on animal studies, whereas the human research supports the safety and benefits of soyfoods. In support of safety is the recent conclusion of the European Food Safety Authority that isoflavones do not adversely affect the breast, thyroid or uterus of postmenopausal women. This review covers each of the major research areas involving soy focusing primarily on the clinical and epidemiologic research. Background information on Asian soy intake, isoflavones, and nutrient content is also provided.
282 citations
Uppsala University1, AstraZeneca2, Katholieke Universiteit Leuven3, Simulations Plus, Inc.4, Janssen Pharmaceutica5, University of Mainz6, Lundbeck7, Medical Products Agency8, Bayer HealthCare Pharmaceuticals9, National and Kapodistrian University of Athens10, University of Manchester11, University of Greifswald12, University of Strathclyde13
TL;DR: This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals with emphasis on in vivo methods for testing and prediction of oral dosage form performance.
253 citations
Cites background from "Metabolic Phenotype of Isoflavones ..."
...However, in vitro and in vivo studies have shown intestinal and hepatic UDP and SULT functionality with potential similarity to humans (Gu et al., 2006; Rahikainen et al., 2013; Sjögren et al., 2012; Thörn et al., 2012)....
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References
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TL;DR: Two new diets may prove to be a better choice than AIN-76A for long-term as well as short-term studies with laboratory rodents because of a better balance of essential nutrients.
Abstract: For sixteen years, the American Institute of Nutrition Rodent Diets, AIN-76 and AIN-76A, have been used extensively around the world. Because of numerous nutritional and technical problems encountered with the diet during this period, it was revised. Two new formulations were derived: AIN-93G for growth, pregnancy and lactation, and AIN-93M for adult maintenance. Some major differences in the new formulation of AIN-93G compared with AIN-76A are as follows: 7 g soybean oil/100 g diet was substituted for 5 g corn oil/100 g diet to increase the amount of linolenic acid; cornstarch was substituted for sucrose; the amount of phosphorus was reduced to help eliminate the problem of kidney calcification in female rats; L-cystine was substituted for DL-methionine as the amino acid supplement for casein, known to be deficient in the sulfur amino acids; manganese concentration was lowered to one-fifth the amount in the old diet; the amounts of vitamin E, vitamin K and vitamin B-12 were increased; and molybdenum, silicon, fluoride, nickel, boron, lithium and vanadium were added to the mineral mix. For the AIN-93M maintenance diet, the amount of fat was lowered to 40 g/kg diet from 70 g/kg diet, and the amount of casein to 140 g/kg from 200 g/kg in the AIN-93G diet. Because of a better balance of essential nutrients, the AIN-93 diets may prove to be a better choice than AIN-76A for long-term as well as short-term studies with laboratory rodents.
7,946 citations
TL;DR: It is now apparent that there are two distinct subpopulations of people and that "bacterio-typing" individuals for their ability to make equol may hold the clue to the effectiveness of soy protein diets in the treatment or prevention of hormone-dependent conditions.
Abstract: Equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman] is a nonsteroidal estrogen of the isoflavone class. It is exclusively a product of intestinal bacterial metabolism of dietary isoflavones and it possesses estrogenic activity, having affinity for both estrogen receptors, ERalpha and ERbeta. Equol is superior to all other isoflavones in its antioxidant activity. It is the end product of the biotransformation of the phytoestrogen daidzein, one of the two main isoflavones found in abundance in soybeans and most soy foods. Once formed, it is relatively stable; however, equol is not produced in all healthy adults in response to dietary challenge with soy or daidzein. Several recent dietary intervention studies examining the health effects of soy isoflavones allude to the potential importance of equol by establishing that maximal clinical responses to soy protein diets are observed in people who are good "equol-producers." It is now apparent that there are two distinct subpopulations of people and that "bacterio-typing" individuals for their ability to make equol may hold the clue to the effectiveness of soy protein diets in the treatment or prevention of hormone-dependent conditions. In reviewing the history of equol, its biological properties, factors influencing its formation and clinical data, we propose a new paradigm. The clinical effectiveness of soy protein in cardiovascular, bone and menopausal health may be a function of the ability to biotransform soy isoflavones to the more potent estrogenic isoflavone, equol. The failure to distinguish those subjects who are "equol-producers" from "nonequol producers" in previous clinical studies could plausibly explain the variance in reported data on the health benefits of soy.
1,143 citations
TL;DR: Differences in the pharmacokinetics of isoflavone glycosides compared with their respective beta-glycosides are demonstrated and indicate a need for improvement in quality assurance and standardization of such products.
Abstract: The pharmacokinetic behavior of naturally occurring isoflavones has been determined for the first time in healthy adults. We compared plasma kinetics of pure daidzein, genistein and their beta-glycosides administered as a single-bolus dose to 19 healthy women. This study demonstrates differences in the pharmacokinetics of isoflavone glycosides compared with their respective beta-glycosides. Although all isoflavones are efficiently absorbed from the intestinal tract, there are striking differences in the fate of aglycones and beta-glycosides. Mean time to attain peak plasma concentrations (t(max)) for the aglycones genistein and daidzein was 5.2 and 6.6 h, respectively, whereas for the corresponding beta-glycosides, the t(max) was delayed to 9.3 and 9.0 h, respectively, consistent with the residence time needed for hydrolytic cleavage of the glycoside moiety for bioavailability. The apparent volume of distribution of isoflavones confirms extensive tissue distribution after absorption. Plasma genistein concentrations are consistently higher than daidzein when equal amounts of the two isoflavones are administered, and this is accounted for by the more extensive distribution of daidzein (236 L) compared with genistein (161 L). The systemic bioavailability of genistein [mean AUC = 4.54 microg/(mL x h)] is much greater than that of daidzein [mean AUC = 2.94 microg/(mL x h)], and bioavailability of these isoflavones is greater when ingested as beta-glycosides rather than aglycones as measured from the area under the curve of the plasma appearance and disappearance concentrations. The pharmacokinetics of methoxylated isoflavones show distinct differences depending on the position of the methoxyl group in the molecule. Glycitin, found in two phytoestrogen supplements, underwent hydrolysis of the beta-glycoside moiety and little further biotransformation, leading to high plasma glycitein concentrations. Biochanin A and formononetin, two isoflavones found in one phytoestrogen supplement, were rapidly and efficiently demethylated, resulting in high plasma genistein and daidzein concentrations typically observed after the ingestion of soy-containing foods. These differences in pharmacokinetics and metabolism have implications for clinical studies because it cannot be assumed that all isoflavones are comparable in their pharmacokinetics and bioavailability. An analysis of 33 phytoestrogen supplements and extracts revealed considerable differences in the isoflavone content from that claimed by the manufacturers. Plasma concentrations of isoflavones show marked qualitative and quantitative differences depending on the type of supplement ingested. These studies indicate a need for improvement in quality assurance and standardization of such products.
899 citations
TL;DR: It is suggested that the dietary fat intake decreases the capacity of gut microbial flora to synthesize equol, and this variation inIsoflavone metabolism is investigated in a crossover study of a soy-containing food low or high in isoflavones.
Abstract: The soy isoflavones, daidzein and genistein, and the lignans, matairesinol and secoisolariciresinol, are phytoestrogens metabolized extensively by the intestinal microflora Considerable important evidence is already available that shows extensive interindividual variation in isoflavone metabolism, and we have investigated the extent of this variation in a crossover study of a soy-containing food low or high in isoflavones (each treatment period lasted for 17 days, and the 2 treatment periods were separated by a 25-day washout period) in 24 healthy subjects [19 women and 5 men, mean age 30 yr, range 19-40, mean body mass index 225 +/- 35 (SD) kg/m2] There was a 16-fold variation in total isoflavonoid excretion in urine after the high-isoflavone treatment period The variation in urinary equol excretion was greatest (664-fold), and subjects fell into two groups: poor equol excretors and good equol excretors (36%) A significant negative correlation was found between the proportion of energy from fat in the habitual diet and urinary equol excretion (r = -055; p = 0012) Good equol excretors consumed less fat as percentage of energy than poor excretors (26 +/- 23% compared with 35 +/- 16%, p < 001) and more carbohydrate as percentage of energy than poor excretors (55 +/- 29% compared with 47 +/- 17%, p < 005) Interindividual variation in the urinary excretion of O-desmethyl-angolensin (O-DMA) was also apparent (76-fold after the high-isoflavone treatment period), but there was no relationship between equol excretion and O-DMA excretion Enterolactone was the major lignan metabolite in urine and plasma but showed less interindividual variation than equol and O-DMA It is suggested that the dietary fat intake decreases the capacity of gut microbial flora to synthesize equol
570 citations
TL;DR: This double-blind, randomized, placebo-controlled trial does not support the hypothesis that the use of soy protein supplement containing isoflavones improves cognitive function, bone mineral density, or plasma lipids in healthy postmenopausal women when started at the age of 60 years or later.
Abstract: ContextPostmenopausal estrogen therapy has been posited to have some beneficial
effects on aging processes, but its use has risks. Isoflavones, estrogenlike
compounds naturally occurring in plant foods, might confer positive effects
with fewer adverse effects.ObjectiveTo investigate whether soy protein with isoflavones improves cognitive
function, bone mineral density, and plasma lipids in postmenopausal women.Design, Setting, and ParticipantsDouble-blind, randomized, placebo-controlled trial of 202 healthy postmenopausal
women aged 60 to 75 years, recruited from a population-based sample in the
Netherlands, conducted between April 2000 and September 2001.InterventionParticipants were randomly assigned to receive 25.6 g of soy protein
containing 99 mg of isoflavones (52 mg genistein, 41 mg daidzein, and 6 mg
glycetein or total milk protein as a powder on a daily basis for 12 months.Main Outcome MeasuresCognitive function was assessed using the following instruments: dementia,
Mini-Mental State Examination; memory, Rey Auditory Verbal Learning Test,
immediate recall, delayed recall, and recognition, the Digit Span forward
and reversed, and the Doors test; complex attention tasks, Digit Symbol Substitution
and Trailmaking, A1, A2, and B; and verbal skills, Verbal Fluency A and N,
animals and occupations, and the Boston Naming Task. Bone mineral density
of the hip and lumbar spine was assessed using dual-energy x-ray absorptiometry
scanning. Lipid assessment included lipoprotein(a), total cholesterol, low-density
lipoprotein, high-density lipoprotein, and triglycerides.ResultsA total of 175 women completed the baseline and at least 1 postintervention
analysis and were included in the modified intent-to-treat analysis. Adherence
was good (median plasma genistein levels, 17.2 and 615.1 nmol/L for placebo
and soy group, respectively). Cognitive function, bone mineral density, or
plasma lipids did not differ significantly between the groups after a year.ConclusionThis double-blind randomized trial does not support the hypothesis that
the use of soy protein supplement containing isoflavones improves cognitive
function, bone mineral density, or plasma lipids in healthy postmenopausal
women when started at the age of 60 years or later.
373 citations