|The Journal of Clinical Endocrinology &
Metabolism Vol. 89, No. 4 1779-1787
Copyright © 2004 by The Endocrine Society
Phytoestrogens Are Potent Inhibitors of Estrogen Sulfation: Implications for Breast Cancer Risk and Treatment
R. M. Harris, D. M. Wood, L. Bottomley, S. Blagg, K. Owen, P. J. Hughes, R. H. Waring and C. J. Kirk
School of Biosciences and Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
Address all correspondence and requests for reprints to: C. J. Kirk, School of Biosciences and Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. E-mail: email@example.com.
We investigated the ability of 37 flavonoids and flavonoid sulfoconjugates, including some abundant dietary constituents, to act as substrates and/or inhibitors of the sulfotransferase and sulfatase enzymes that interconvert active estrogens and inactive estrogen sulfates in human tissues. The enzymes studied include estrogen sulfotransferase, the thermostable phenolsulfotransferase that acts on a range of substrates including estrogens; steroid sulfatase; and two related enzymes, monoamine phenolsulfotransferase and arylsulfatase A. Several dietary flavonoids, including the soy isoflavones genistein and daidzein, were sulfated by these human sulfotransferases. Many flavonoids were potent inhibitors of thermostable phenolsulfotransferase. Genistein and equol were potent mixed inhibitors of hepatic estrogen sulfotransferase, with inhibitory constant values of 500 nM and 400 nM, respectively. Monoamine phenolsulfotransferase activity was relatively unaffected by flavonoids, but this enzyme was mainly responsible for the sulfation of flavonoids at concentrations greater than 1 µM. Of the compounds tested, only daidzein 4,7-bisulfate, a trace metabolite in humans, significantly inhibited steroid sulfatase in the micromolar concentration range. Hence, dietary flavonoids may be able to influence the bioavailability of endogenous estrogens, and disrupt endocrine balance, by increasing the ratio of active estrogens to inactive estrogen sulfates in human tissues.
Psychopharmacology (Berl) 2003 Apr;167(1):46-53
The soya isoflavone content of rat diet can increase anxiety and stress hormone release in the male rat.
Hartley DE, Edwards JE, Spiller CE, Alom N, Tucci S, Seth P, Forsling ML, File SE. Psychopharmacology Research Unit, Centre for Neuroscience, Hodgkin Building, Kings College London, Guy's Campus, SE1 1UL, London, UK, firstname.lastname@example.org
RATIONALE. Most commercial
rodent diets are formulated with soya protein and therefore contain
soya isoflavones. Isoflavones form one of the main classes of phytoestrogens
and have been found to exert both oestrogenic and anti-oestrogenic effects
on the central nervous system. The effects have not been limited to reproductive
behaviour, but include effects on learning and anxiety and actions on
the hypothalamo-pituitary axis. It is therefore possible that the soya
content of diet could have significant effects on brain and behaviour
and be an important source of between-laboratory variability.
Eur J Clin Nutr 2003 Jan;57(1):100-6
Dietary supplements of soya flour lower serum testosterone concentrations and improve markers of oxidative stress in men.
Gardner-Thorpe D, O'Hagen C, Young I, Lewis SJ Department of Medicine, University Hospital of Wales, Cardiff, Wales, UK.
We examined the effects on serum sex steroids, lipids and markers of oxidative
stress of supplementing the diets of healthy male volunteers with scones
made with soya flour.
[So, does eating soy products lead to male homosexuality? - ljf]
J Nutr 2002 Aug;132(8):2283-7
A high isoflavone soy protein diet and intravenous genistein delay rejection of rat cardiac allografts.
O'Connor TP, Liesen DA, Mann PC, Rolando L, Banz WJ Department of Surgery, Southern Illinois University School of Medicine, Springfield 62702, USA. email@example.com
Genistein, a soy isoflavone, has in vitro immunosuppressive properties. [Suppressing the immunological system so it can not protect the organism is not a good idea! - ljf] We investigated whether genistein or dietary soy protein containing isoflavones could influence the outcome of rat cardiac allografts. Lewis rats were fed a diet with protein from high isoflavone soy protein fraction (HIS), casein (CAS) or casein with isoflavones added (CI) starting 1 wk before heart transplants from Wistar Furth donors, and continuing throughout the study. HIS-fed rats had significantly prolonged time to rejection compared with CAS- and CI-fed recipients (10.8 +/- 2.62 vs. 7.18 +/- 0.75 and 7.22 +/- 0.44 d, P < 0.001). Intravenous genistein [20mg/(kg. d) for 14 d] significantly prolonged heart survival compared with controls and dissolvent-treated recipients (23.2 +/- 7.4 vs. 8.4 +/- 1.3 and 11.4+/3.6 d, P < 0.0005), and had an additive effect when given to heart recipients also receiving low dose cyclosporine for 7 d (30.8 +/- 2.3 vs. 23.4 +/- 2.4 d, P < 0.005). Concanavalin A-stimulated lymphocytes, isolated from Lewis rats given intraperitoneal genistein for 7 d, had decreased production of interferon gamma compared with controls or dimethyl sulfoxide-treated groups (22.6 +/- 9.9 vs 149 +/- 105 and 154 +/- 103 micro g/L, P < 0.05). In conclusion, a high isoflavone soy diet and intravenous genistein, but not isoflavone extract alone, delay rejection of rat cardiac allografts, with an additive effect in cyclosporine-treated rats. In addition, intraperitoneal genistein has immunosuppressive properties in vivo.
Arch Pediatr 2001 Nov;8(11):1226-33
[Infant formulas and soy protein-based formulas: current data] [Article in French]
Bocquet A, Bresson JL, Briend A, Chouraqui JP, Darmaun D, Dupont C, Frelut ML, Ghisolfi J, Goulet O, Putet G, Rieu D, Turck D, Vidailhet M; Comite de Nutrition de la Societe Francaise de Pediatrie. Service de pediatrie II, hopital Arnaud-de-Villeneuve, 371, avenue du Doyen-Giraud, 34295 Montpellier, France.
For many years soy bean-based formulas (SBBF) were the only dietary product used for infants with cow's milk intolerance. At the present time, their place in infant nutrition is reduced as a result of the availability of new dietary products without lactose and/or cow's milk proteins and the recognition of soy bean protein allergy. There is no evidence that SBBF have any efficiency in infant colic. SBBF have no indication in the prevention of allergy, nor in premature infants' nutrition. Their main indication is the feeding of infants of vegetarian parents who do not want to use cow's milk products. Studies have shown that SBBF contain large quantities of phytoestrogens, particularly isoflavone. Because of experimental data suggesting a possible deleterious effect of phytoestrogens on the neuroendocrine maturation, the reduction of their content in SBBF must be considered.
Reprod Toxicol 2001 Mar-Apr;15(2):105-10
Placental transfer of the soy isoflavone genistein following dietary and gavage administration to Sprague Dawley rats.
Doerge DR, Churchwell MI, Chang HC, Newbold RR, Delclos KB. Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, 72079, Jefferson, AR, USA
Genistein, the principal soy isoflavone, has estrogenic activity and is widely consumed by humans for putative beneficial health effects. The goal of the present study was to measure placental transfer of genistein in rats as a possible route of developmental exposure. Pregnant Sprague-Dawley rats were administered genistein orally, either by diet or by gavage. Concentrations of genistein aglycone and conjugates were measured in maternal and offspring serum and brain using HPLC with isotope dilution electrospray tandem mass spectrometry. Although fetal or neonatal serum concentrations of total genistein were approximately 20-fold lower than maternal serum concentrations, the biologically active genistein aglycone concentration was only 5-fold lower. Fetal brain contained predominately genistein aglycone at levels similar to those in the maternal brain. These studies show that genistein aglycone crosses the rat placenta and can reach fetal brain from maternal serum genistein levels that are relevant to those observed in humans.
Br J Nutr 2001 Apr;85(4):447-457
Activation of skeletal muscle protein breakdown following consumption of soyabean protein in pigs.
Lohrke B, Saggau E, Schadereit R, Beyer M, Bellmann O, Kuhla S, Hagemeister H. Research Institute for Biology of Farm Animals, Dummerstorf-Rostock, Department of Animal Nutrition, Germany. firstname.lastname@example.org.
Diets with protein of inferior quality may increase protein breakdown in skeletal muscle but the experimental results are inconsistent. To elucidate the relationship, pigs were fed isoenergetic and isonitrogenous diets based on soyabean-protein isolate or casein for 15 weeks, with four to six animals per group. A higher plasma level of urea (2.5-fold the casein group value, P = 0.01), higher urinary N excretion (2.1-fold the casein group value, P = 0.01), a postabsorptive rise in the plasma levels of urea, 3-methylhistidine and isoleucine in soyabean protein-fed pigs suggested recruitment of circulatory amino acids by protein breakdown in peripheral tissues. Significant differences between dietary groups were detected in lysosomal and ATP-dependent proteolytic activities in the semimembranosus muscle of food-deprived pigs. A higher concentration of cathepsin B protein was found, corresponding to a rise in the cathepsin B activity, in response to dietary soyabean protein. Muscle ATP-stimulated proteolytical activity was 1.6-fold the casein group value (P = 0.03). A transient rise in the level of cortisol (2.9-times the casein group value, P = 0.02) occurred in the postprandial phase only in the soyabean group. These data suggest that the inferior quality of dietary soyabean protein induces hormonally-mediated upregulation of muscle protein breakdown for recruitment of circulatory amino acids in a postabsorptive state.
Brain Res Dev Brain Res 2001 Feb 28;126(2):217-21
Maternal and perinatal brain aromatase: effects of dietary soy phytoestrogens.
Weber KS, Setchell KD, Lephart ED. 633 WIDB, Neuroscience Center, Brigham Young University, Provo, UT 84602, USA.
Phytoestrogens are extensively investigated for their potential to prevent many hormone-dependent cancers and age-related diseases, however little is known about their effects in brain. Brain aromatase and plasma phytoestrogen levels were determined in Sprague-Dawley rats fed a phytoestrogen-rich diet during pregnancy/lactation. Ingested phytoestrogens cross the placenta and become concentrated in maternal milk as evident from high infantile plasma concentrations. Dietary phytoestrogens, however, do not alter brain aromatase during pregnancy/lactation or perinatal development.
J Am Coll Nutr 2000 Apr;19(2):242-55 Comment in: J Am Coll Nutr. 2000 Apr;19(2):207-9
Brain aging and midlife tofu consumption.
White LR, Petrovitch H, Ross GW, Masaki K, Hardman J, Nelson J, Davis D, Markesbery W. National Institute on Aging, NIH, USA.
OBJECTIVE: To examine associations of midlife tofu consumption with brain function and structural changes in late life. METHODS: The design utilized surviving participants of a longitudinal study established in 1965 for research on heart disease, stroke, and cancer. Information on consumption of selected foods was available from standardized interviews conducted 1965-1967 and 1971-1974. A 4-level composite intake index defined "low-low" consumption as fewer than two servings of tofu per week in 1965 and no tofu in the prior week in 1971. Men who reported two or more servings per week at both interviews were defined as "high-high" consumers. Intermediate or less consistent "low" and "high" consumption levels were also defined. Cognitive functioning was tested at the 1991-1993 examination, when participants were aged 71 to 93 years (n = 3734). Brain atrophy was assessed using neuroimage (n = 574) and autopsy (n = 290) information. Cognitive function data were also analyzed for wives of a sample of study participants (n = 502) who had been living with the participants at the time of their dietary interviews. RESULTS: Poor cognitive test performance, enlargement of ventricles and low brain weight were each significantly and independently associated with higher midlife tofu consumption. A similar association of midlife tofu intake with poor late life cognitive test scores was also observed among wives of cohort members, using the husband's answers to food frequency questions as proxy for the wife's consumption. Statistically significant associations were consistently demonstrated in linear and logistic multivariate regression models. Odds ratios comparing endpoints among "high-high" with "low-low" consumers were mostly in the range of 1.6 to 2.0. CONCLUSIONS: In this population, higher midlife tofu consumption was independently associated with indicators of cognitive impairment and brain atrophy in late life.
J Nutr 1995 Feb;125(2):212-9
A vegetarian diet rich in soybean products compromises iron status in young students.
Shaw NS, Chin CJ, Pan WH. Department of Agricultural Chemistry, National Taiwan University, Taipei, Republic of China.
The iron status of young Chinese Buddhist vegetarians (23 men and 32 women) and nonvegetarian students (20 men and 39 women from a medical college) was investigated by dietary assessment of iron intake and hematological measurement of biochemical indices including hemoglobin, plasma iron, transferrin, transferrin saturation and plasma ferritin. A characteristic of the vegetarian diet in this study was the replacement of meat by soybean products. Results of the dietary assessment showed that the average iron density of the diets ranged from 1.9 to 2.2 mg/MJ, with no difference between the vegetarian and nonvegetarian diets. Daily iron intake was similar in both vegetarian and nonvegetarian men. However, iron intake was significantly higher in female vegetarians than nonvegetarians, averaging 104 and 78% of the RDA, respectively. Results of blood analysis showed that, for both sexes, the median plasma ferritin concentration of the vegetarians (male 47 micrograms/L and female 12 micrograms/L) was about half the level of the nonvegetarians (male 91 micrograms/L and female 27 micrograms/L). Occurrence and risk of iron deficiency are more prevalent in vegetarians. Correlation between plasma ferritin concentration and years of vegetarian practice in vegetarian men was marginally significant (r = -0.38, P = 0.077). We conclude that a vegetarian diet that is rich in soybean products and restricted in animal foods is limited in bioavailable iron and is not adequate for maintaining iron balance in men and women.
Brain Res Bull 1986 Aug;17(2):189-95
Perinatal dietary supplementation with a soy lecithin preparation: effects on development of central catecholaminergic neurotransmitter systems.
Bell JM, Whitmore WL, Cowdery T, Slotkin TA.
Previous work has shown that exposure of developing rats to soy lecithin preparations (SLP) influences macromolecular constituents of immature brain cells and causes abnormal behavioral patterns. To determine if synaptic mechanisms are adversely affected by SLP, we examined the developmental characteristics of noradrenergic and dopaminergic pathways in discrete brain regions. Although transmitter levels were unaffected, the utilization rates of both catecholamines were profoundly disturbed in an age-dependent, regionally-selective manner. Utilization tended to be subnormal in the preweanling stage, but demonstrated a postweaning elevation in cerebellum and midbrain + brainstem. Enhanced utilization persisted in the latter region only, and cerebral cortex actually showed a lowered utilization rate in adulthood (60 days of age). Transmitter uptake capabilities were also affected by developmental exposure to SLP, as was tyrosine hydroxylase activity. The patterns of effects on these two variables indicated that the altered transmitter utilization rate probably reflected a change in impulse activity in the affected neuron populations, with promotion of activity in the midbrain + brainstem and reduced activity in the cerebral cortex. These data indicate that dietary supplementation with SLP throughout perinatal development alters synaptic characteristics in a manner consistent with disturbances in neural function.