Presentazione sul tema: "Fitoestrogeni. DNA pol a Cyclins E,A B-Myb Estrogen Receptor."— Transcript della presentazione:
DNA pol a Cyclins E,A B-Myb
Estrogen Receptors ER- –Uterus, testis, pituitary, ovary, epididymis, and adrenal gland. ER- (Kuiper et al. 1996) –brain, kidney, prostrate, ovary, lung, bladder, intestine, and epididymis. –88% identity with rat ER- identity with human ER- Membrane localized ER (Pietras and Szego, 1997) ER and 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 J. Biol. Chem., 276:
ER effects on different cell types
Estrogen has multiple effects
Ligand Induces a Conformational Change in the LBD that Repositions helix 12 No LigandAgonist
NR Antagonists Alter the Position of Helix 12 No Ligand Agonist (ER) Antagonist (ER)
Phytoestrogens Aherne and OBrien, Nutrition 18:75-81.
Benassayag, et al., J. Chromatogr.B 777:
Comparison of binding affinities and transactivation of estrogen and phytoestrogens Belcher & Zsarnovszky, J. Pharmacol. Exp. Therap. 299:
Dietary Sources of Phytoestrogens
Pytoestrogens in humans Fitoestrogeni hanno una attivita piu debole di quella degli estrogeni circolanti (17- -estradiol or estrone). Fitoestrogeni possono legarsi alla sex steroid binding protein (SBP) e -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 M che sono livelli simili alle urine.
Fitoestrogeni (PEs) della Soia Genistein, daidzein, coumesterol, and equol si legano e transattivano ER and ( M) Genistetin ha una affinita piu alta per ER. Soia PEs influenzano la progressione del ciclo cellulare, crescita e differenziamento. Hanno attivita antiossidanti.
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- B and AP-1 pathways. Resveratrol inhibits protein kinase C, Akt, and FAK activities in ER (+) breast cancer cells. Red wine phytoestrogens: Resveratrol, quercetin, and anthocyanins
Genistein Both estrogenic and anti-estrogenic effects Inhibitor of tyrosine kinases 20-fold higher binding affinity for ER- than ER- (Makela et al. 1999) Genistein [ ] Synonyms: 4',5,7-Trihydroxyisoflavone; Synonyms: 4',5,7-Trihydroxyisoflavone; Synonyms: 4',5,7-Trihydroxyisoflavone; Synonyms: 4',5,7-Trihydroxyisoflavone; Synonyms: 4',5,7-Trihydroxyisoflavone; Synonyms: 4',5,7-Trihydroxyisoflavone; 4',5,7-Trihydroxyisoflavone
Phytoestrogens in Human Health Cancer preventive Post-menopausal supplement Prevention of osteoporosis Cardiovascular health Fertility Breast enhancement References: Kurzer, J. Nutr. 133: 1983S-1986S. Benassayag, et al., J. Chromatogr.B 777:
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 ER (-) breast cancer cells. Therefore, ER 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 Womens 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 post- menopausal osteoporosis. Diets rich in phytoestrogens can protect long-term bone loss (Setchell & Lydeking-Olsen, Am. J. Clin. Nutr. 78:593S- 609S).
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)