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Fitoestrogeni

Fitoestrogeni. ER in cell cycle progression. Myc. ER. Cdc25A. CyclinD1 Cdk4. CyclinE Cdk2. E2F. Rb. DNA pol a Cyclins E,A B-Myb. G1. S. Estrogen Receptor. Estrogen Receptors. http://www.bio.cmu.edu/Courses/BiochemMols/ER/#ERchime. Estrogen Receptors. ER- a

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Fitoestrogeni

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  1. Fitoestrogeni

  2. ER in cell cycle progression Myc ER Cdc25A CyclinD1 Cdk4 CyclinE Cdk2 E2F Rb DNA pol a Cyclins E,A B-Myb G1 S

  3. Estrogen Receptor

  4. Estrogen Receptors http://www.bio.cmu.edu/Courses/BiochemMols/ER/#ERchime

  5. 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.

  6. Estradiol Growth factors MAPK P P P P P DBD AF-1 AF-2 AH

  7. Regulation of ER activity by coactivators and corepressors

  8. Estrogen Signaling Hall et al. 2001. J. Biol. Chem., 276: 36869-36872

  9. ER effects on different cell types

  10. Estrogen has multiple effects

  11. Antiestrogens can stop harmful effects of estrogen

  12. Ligand Induces a Conformational Change in the LBD that Repositions helix 12 No Ligand Agonist

  13. NR Antagonists Alter the Position of Helix 12 Agonist (ER) Antagonist (ER) No Ligand

  14. SERMs (Selective Estrogen Receptor Modulators)

  15. Phytoestrogens Aherne and O’Brien, 2002. Nutrition 18:75-81.

  16. Phytoestrogens Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.

  17. Comparison of binding affinities and transactivation of estrogen and phytoestrogens Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414

  18. Dietary Sources of Phytoestrogens

  19. 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.

  20. 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.

  21. 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.

  22. Genistein • 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) 4',5,7-Trihydroxyisoflavone

  23. 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.

  24. 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.

  25. 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%.

  26. Prevention of osteoporosis • Isoflavone intake increases bone mineral density. • Can be useful in preventing post-menopausal osteoporosis. • Diets rich in phytoestrogens can protect long-term bone loss (Setchell & Lydeking-Olsen, 2003. Am. J. Clin. Nutr. 78:593S-609S) .

  27. 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.

  28. 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)

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