DNA pol a
– Uterus, testis, pituitary, ovary, epididymis, and adrenal gland.
• ER-b (Kuiper et al. 1996)
– brain, kidney, prostrate, ovary, lung, bladder, intestine, and
– 88% identity with rat ER-b;
47% identity with human ER-a
• Membrane localized ER (Pietras and Szego, 1997)
• ERa and b differ in C-terminal ligand binding domains
and N-terminal transactivation domains. Highest
homology in DNA binding domain.
Regulation of ER activity by
coactivators and corepressors
Hall et al. 2001. J. Biol. Chem., 276: 36869-36872
ER effects on different cell types
Estrogens can activate growth
factor receptor signaling
Levin ER. Mol.Endocrinol. 2003;17:309-17
Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414.
Estrogen has multiple effects
Aherne and O’Brien, 2002. Nutrition 18:75-81.
Benassayag, et al., 2002. J. Chromatogr.B
Comparison of binding affinities and
transactivation of estrogen and phytoestrogens
Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414
Dietary Sources of Phytoestrogens
Pytoestrogens in humans
• Phytoestrogens have weaker estrogenic activity compared
to circulating estrogens (17-b-estradiol or estrone).
• Phytoestrogens can bind sex steroid binding protein (SBP)
and a-feroprotein (AFP) and be circulated.
• Dietary phytoestrogens are metabolised by intestinal
bacteria, absorbed, conjugated in the liver (by
sulfotransferases and UDP-glucoronyosyl transferases),
circulated in plasma and excreted in urine.
• Phytoestrogen levels are higher in fluid collected from
breast and prostatic ducts compared with serum or
• Urinary isoflavonoid excretions range from about 0.3-30
• Urinary secretions of vegetarians may contain 1000 times
higher phytoetsrogens than total urinary steroid estrogens.
• Phytoestrogens demonstrate inhibitory effects at 0.5-50mM
which are similar to levels in urine.
• Genistein, daidzein, coumesterol, and equol bind to and
transactivate both ER a and b (0.1-10mM)
• Genistetin has a higher affinity for ERb.
• Soy PEs effect cell cycle progression, growth, and
differentiation. Have antioxidant and anti-angiogenic
• Genistein affects cellular function via inhibition of 17 beta-
steroid oxidoreductase (an enzyme necessary for
conversion of androgens to E2).
• Inhibits aromatase.
• Effects cycloxygenase, lipoxygenase, Cholesterol 7a
• Modulates the activity of topoisomerase II.
• Modulates enzymes involved in phosphoinositide (PI)
• Modulates TGF-β signaling cascades
• Increases epidermal growth factor (EGF) and EGFR levels.
• Both estrogenic and anti-estrogenic
y • Inhibitor of tyrosine kinases
r • 20-fold higher binding affinity for ER-b
x than ER-a (Makela et al. 1999)
Phytoestrogens in Human Health
• Cancer preventive
• Post-menopausal supplement
• Prevention of osteoporosis
• Cardiovascular health
• Breast enhancement
References: Kurzer, 2003. J. Nutr. 133: 1983S-1986S.
Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.
• Benefits to human breast and uterine cancer
• Genistein can be carcinogenic in uterine cancer at
• Cancer protective in animal studies, especially when
exposed during breast development.
• Isoflavonoids and lignans stimulate proliferation of ER+
breast cancer cells.
• Inhibit cell growth at high concentrations and in ERa (-)
breast cancer cells.
• Therefore, ER b may have cancer protective effect.
• Anti-angiogenic effects of genistein, daidzein, and
biochanin A may contribute to antitumor activity.
• Anti-oxidants in vitro and in vivo.
• In 2002, the Women’s Health Initiative
(WHI) trial of estrogen/progestin therapy
was halted midtrial due to high incidence
of breast cancer and cardiovascular
• Consumption of 30mg/d soy isoflavones
may reduce hot flashes by 30-50%.
Prevention of osteoporosis
• Isoflavone intake increases bone
• Can be useful in preventing post-
• Diets rich in phytoestrogens can
protect long-term bone loss (Setchell &
Lydeking-Olsen, 2003. Am. J. Clin. Nutr. 78:593S-
• Average intake of 47g/day soy protein results
in 9% decrease in total cholesterol,13%
decrease in LDL cholesterol, and a trend
towards HDL cholesterol.
• Flavanoids decrease platelet aggregation.
• Genistein-induced inhibition of growth factor
activity can interfere with platelet and thrombin
Effects on fertility (premenopausal)
• Interferes with menstrual cycle (delay)
Reduced LH and FSH and progesterone.
• Male rodents exposed to PEs in early life:
impaired semen quality, congenital
malformations, testicular cancer
(coumesterol, delay in mating)
Red wine phytoestrogens:
Resveratrol, quercetin, and anthocyanins
• Antioxidant, anti-apoptosis, anti-inflammatory, anti-cancer, and
• Reduces Cu-induced LDL oxidation by binding to LDL via a glycosidic
ether bond. Increases HDL cholesterol. Inhibits platelet activation.
• Ameliorates neuronal damage due to ethanol consumption. Probably
via antioxidant effect. Minimizes effects of NOS activity by ehtanol.
Inhibits ethanol-induced arachidonic acid release and cycloxygenase
• inhibitory effects on cancer initiation, growth promotion progression
and angiogenesis in model systems.
• The anti-proliferative activity of resveratrol is mediated by p38-MAPKs
via p53 mediated inhibition. Resveratrol may inhibit apoptosis induced by
oxidized lipoproteins through inhibition of NF-kB and AP-1 pathways.
• Resveratrol inhibits protein kinase C, Akt, and FAK activities in ER a (+)
breast cancer cells.