Fitoestrogeni
DNA pol a
Cyclins E,A
B-Myb
Estrogen Receptor
Estrogen Receptors
http://www.bio.cmu.edu/Courses/BiochemMols/ER/#ERchime
Estrogen Receptors
• ER-a
– Uterus, testis, pituitary, ovary, epididymis, and adrenal gland.
• ER-b (Kuiper et al. 1996)
– brain, kidney, prostrate, ovary, lung, bladder, intestine, and
epididymis.
– 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
Estrogen has multiple effects
Ligand Induces a Conformational Change in
the LBD that Repositions helix 12
No Ligand
Agonist
NR Antagonists Alter the Position of Helix 12
No Ligand
Agonist
(ER)
Antagonist
(ER)
Phytoestrogens
Aherne and O’Brien, 2002. Nutrition 18:75-81.
Benassayag, et al., 2002. J. Chromatogr.B
777:233-248.
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
• Fitoestrogeni hanno una attivita’ piu’ debole di quella degli
estrogeni circolanti (17-b-estradiol or estrone).
• Fitoestrogeni possono legarsi alla sex steroid binding
protein (SBP) e a-feroprotein (AFP) e circolare.
• Fitoestrogeni sono coniugati nel fegato (da sulfotransferasi
and UDP-glucoronyosyl transferasi), circolano nel plasma
ed escreti nelle urine.
• Livelli di Fitoestrogeni sono piu’ alti nei fluidi dei dotti
prostatici e mammari di quelli del plasma.
• Le urine dei vegetariani possono contenere 1000 volte piu’
Fitoestrogeni che estrogeni totali.
• Fitoestrogeni hanno effetti inibitori a 0.5-50mM che sono
livelli simili alle urine.
Fitoestrogeni (PEs) della Soia
• Genistein, daidzein, coumesterol, and equol si legano e
transattivano ER a and b (0.1-10mM)
• Genistetin ha una affinita’ piu’ alta per ERb.
• Soia PEs influenzano la progressione del ciclo cellulare,
crescita e differenziamento. Hanno attivita’ antiossidanti.
Red wine phytoestrogens:
Resveratrol, quercetin, and anthocyanins
• Antioxidant, anti-apoptosis, anti-inflammatory, anti-cancer, and
anti-invasive.
• 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
activity.
Anti-ageing role?
• 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.
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Genistein
4',5,7-Trihydroxyisoflavone
• Both estrogenic and anti-estrogenic
effects
• Inhibitor of tyrosine kinases
• 20-fold higher binding affinity for ER-b
than ER-a (Makela et al. 1999)
Phytoestrogens in Human Health
•
•
•
•
•
•
Cancer preventive
Post-menopausal supplement
Prevention of osteoporosis
Cardiovascular health
Fertility
Breast enhancement
References: Kurzer, 2003. J. Nutr. 133: 1983S-1986S.
Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.
Cancer preventive
• Benefits to human breast and uterine cancer
controversial.
• Genistein can be carcinogenic in uterine cancer at
neonatal exposure.
• 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.
Post-menopausal therapy
• 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
disease.
• Consumption of 30mg/d soy isoflavones
may reduce hot flashes by 30-50%.
Prevention of osteoporosis
• Isoflavone intake increases bone
mineral density.
• Can be useful in preventing postmenopausal osteoporosis.
• Diets rich in phytoestrogens can
protect long-term bone loss (Setchell &
Lydeking-Olsen, 2003. Am. J. Clin. Nutr. 78:593S609S)
.
Cardiovascular health
• 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
action.
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)