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Phytoestrogens web biosci utexas edu

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					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
       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
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
• 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
  plasma.
• Urinary isoflavonoid excretions range from about 0.3-30
  mM/day.
• 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.
              Soy Phytoestrogens
• 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
  activities.
• 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
  hydroxylase.
• Modulates the activity of topoisomerase II.
• Modulates enzymes involved in phosphoinositide (PI)
  turnover.
• Modulates TGF-β signaling cascades
• Increases epidermal growth factor (EGF) and EGFR levels.
m
s
:
        Genistein
4
'
,
5                               4',5,7-Trihydroxyisoflavone
,
7
-
T
r
    • Both estrogenic and anti-estrogenic
i     effects
h
y   • Inhibitor of tyrosine kinases
d
r   • 20-fold higher binding affinity for ER-b
o
x     than ER-a (Makela et al. 1999)
y
i
s
o
f
    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 post-
  menopausal osteoporosis.
• Diets rich in phytoestrogens can
  protect long-term bone loss (Setchell &
 Lydeking-Olsen, 2003. 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)
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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