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STEROID
HORMONE/NUCLEAR
RECEPTORS
Dec. 2001
Steroid Biosynthesis
Derived from cholesterol
Progesterone receptor A, B
(PRA, PRB)
Androgen receptor (AR)
Glucocorticoid
receptor (GR)
Estrogen receptor α, β
(ERα, ERβ)
Mineralocorticoid receptor (MR)
Glucocorticoids: Therapeutic Uses
Endocrine Disorders:
-acute or chronic adrenal insufficiency
-congenital adrenal hyperplasia
Non-endocrine Disorders:
-rheumatoid arthritis
-bronchial asthma
-inflammatory bowel disease
-inflammatory dermatosis
-organ transplantation
-allergic diseases
-occular diseases
Dec. 2001
Glucocorticoids: Side Effects
Dec. 2001
Dec. 2001
Schematic representation of the disposition of inhaled drugs
Mouth
Deposition
~90% swallowed
Lung
Pulmonary
absorption
Lung
Topical effect
~2-10%
Liver
GI Tract
Drug
Dec. 2001
First pass
Metabolism
(inactivation)
BLOOD STREAM
systemic effect + inactive metabolite
New Approaches for Glucocorticoid
Treatment of Asthma
fluticasone propionate (Flovent ®)
cytochrome P450 3A4
(Liver)
FP-17ß-carboxylic acid derivative
(INACTIVE)
Dec. 2001
COOH
Nuclear Localization of Steroid Receptors
Unliganded
GR
Liganded
GR
Unliganded/
Liganded ER
NOTE:
Steroid Receptors Shuttle Between the Nucleus & Cytoplasm
Dec. 2001
Dec. 2001
Ligands for Various Orphan Receptors
Dec. 2001
Metabolic Pathways of Nuclear Receptor Ligands
Dec. 2001
Chawla et al Science 294:1866, 2001
Dec. 2001
•Active ingredient of Gugulipid
•Gum resin of Commiphor mukl
•In use since 600 BC
•Antagonist of FXR
•(Farnesoid or Bile Acid Receptor)
•Lowers cholesterol and triglyceride
levels
•Active ingredient in St. John’s Wart
•Extract of Hypericum perforatum
•In use over 2000 years
•Ligand for PXR
(Pregnane X or Xenobiotic Receptor)
•Induction of CYP3A4
Dec. 2001
Steroid Hormone Receptors: Limited Forms
Hormone
Receptor(s)
Androgen
AR
Mineralocorticoids
MR
Estrogens
ERa
ERb
Progesterone
PRA
PRB
Glucocorticoids
GR
GRb
Dec. 2001
TWO RECEPTORS FOR ESTROGEN
ERa & ERb
AF-1
DBD
LBD
AF-2
ER-a
ER-b
Homology:
23%
86%
24%
58%
12%
Note: Both types of ER can form homodimers (e.g. ERa/ERa)
or heterodimers (i.e. ERa/ERb)
Estrogen Receptor Distribution Within the Body
ERb
ERa, ERb
Dominant Roles for Select ER Subtypes
ERa
• Stimulation of uterine
growth
• Bone metabolism
• Mammary gland
development
• Negative feedback in
hypothalamus
ERß
• Apoptosis in prostate cancer
cells
• Enhancement of glucose
stimulated insulin secretion
(pancreatic ß cells)
• Folliculogenesis
• Reduced intestinal
inflammation (reduced colon
carcinoma risk)
EMERGING RESEARCH
SELECTIVE ER ISOFORM AGONISTS
NONSTEROIDAL ER ACTIVATORS
Phytoestrogens (from soy)
• Contain flavinoids (e.g. Genistein), which are
weakly estrogenic
Schaefer O, et al., (2003) 8-Prenyl naringenin
is a potent ERalpha selective phytoestrogen
present in hops and beer. J Steroid Biochem
Mol Biol Vol. 84: pp 359-360.
NONSTEROIDAL ER ACTIVATORS
Xenoestrogens or Environmental Estrogens
• Industrial chemicals or their byproducts with
estrogenic activity
• Effects on human health are controversial but
recent studies suggest that long term exposure (i.e.
BPA) may increase risk of obesity and breast cancer in
women
Polychlorobiphenyls (PCBs)
Bisphenol (BPA)
NONSTEROIDAL ER ACTIVATORS
Diethylstilbestrol (DES)
• DES is a potent nonsteroidal estrogen that is not
rapidly metabolized
• DES was prescribed between 1948 and 1971 to
prevent miscarriages in high risk pregnancies
• It’s use was discontinued after female offspring of
women taking DES during pregnancy were found to
have an increased risk of rare cancer (vaginal clear
cell adenocarcinoma).
Dec. 2001
Glucocorticoid Response Unit of the PEPCK Gene
HNF4
HNF3
GR GR
COUP
-445
-410
-380
-325
CEBP/ß
-90
TBP
+1
-27
Accessory DNA-binding Factors
Required!!
(Can impart tissue-specificity)
NOTE: Phosphoenolpyruvate carboxykinase (PEPCK) gene
is glucocorticoid
regulated in liver only
Dec.
2001
Estrogen Regulated Promoters
Association of other Transcription Factors
FH + ER
ER
Genome wide
analysis
(from Myles
Brown Lab)
FH
FH ER
ER
FH
ER
DNA-Induced Conformational Changes in Glucocorticoid Receptor:
Impact on Gene Regulatory Properties
Transcriptional
Activation
Transcriptional Repression
GR Only
GR + Other Transcription Factors
GR
GR
GR
GR
GR
Dec. 2001
Direct DNA binding
Direct DNA Binding
Tethering
CHROMATIN: Higher Order DNA
Compaction Within the Nucleus
Histone Core:
2 copies each of H2A,
H2B, H3, H4 (all basic
proteins-rich in Arg,
Dec.
Lys2001
residues)
Histone Acetylation/Deacetylation
Dec. 2001
Other transcription
factors
NOTE: Rubinstein-Taybi
Syndrome caused by
mutations in CBP.
NOTE: Overexpression of some
coactivators (e.g. Amplified in
Breast Cancer-1 [AIB-1]) associated
with hormone-independent breast
cancer
Dec. 2001
(From Glass and Rosenfeld)
Other transcription
factors
NOTE: HDAC inhibitors in
clinical trials for cancer
treatment
Dec. 2001
(From
Glass and Rosenfeld)
Nuclear Receptors as Drug Targets
• Reproductive or Endocrine Disorders
• Hormone-dependent Cancers (ER-breast cancer,
AR- prostate cancer)
• Metabolic Diseases (PPAR- for Type 2 Diabetes and
Metabolic Syndrome)
NOTE: Ligands for nuclear receptors are small
ligands that are cell permeable
CELL OR TISSUE-SPECIFIC LIGANDS POSSIBLE?
Dec. 2001
Steroid Hormone Action
Action
Estrogen receptor ligandselicit different tissue-specific responses
raloxifene
Z-pseudo
diethylstilbestrol
estradiol
O
4-hydroxytamoxifen
( Z-OHT)
N
O
N
OH
OH
Estrogen
target tissues
OH
O
HO
HO
HO
S
HO
Breast
agonist
agonist
antagonist
Uterus
agonist
partial agonist
antagonist
partial agonist
Bone
agonist
agonist
partial agonist
Liver
agonist
agonist
????
partial agonist
CNS
agonist
agonist
agonist
antagonist
antagonist
antagonist
Selective Estrogen Receptor Modulators (SERMs)
Dec. 2001
Estrogen Receptor Ligand-binding Domain: Ligand-induced
Conformational Change
Helix 12 Contacts:
Coactivator proteins!
Dec. 2001
Dec. 2001
MECHANISM OF SERM ACTION
SERM as Agonist
Recruitment of
Coactivators!
(e.g. Tamoxifen in
uterus)
SERM as Antagonist
Recruitment of
Corepressors! (e.g.
Tamoxifen in breast)
Dec. 2001
THERAPEUTIC ANDROGEN PREPARATIONS
Anabolic Steroids
Greatest Ratio of Protein Anabolic Effects (i.e.
increase in muscle mass) To Virilizing Effects
Oxandrolone
Stanozolol
Dec. 2001
THERAPEUTIC ANDROGEN PREPARATIONS
Anabolic Steroids
Tetrahydrogestrinone (THG)
• Metabolized quickly and had been
difficult to detect since it degrades
during standard gas chromatography
and mass spectrometry procedures
• ~20% potency of DHT in stimulating
prostate, seminal vesicle and levator
ani muscle weight in the mouse
• Toxicity profile unknown
Dec. 2001
Current Status of SARMs
Bhasin S et al. (2006) Nat Clin Pract Endocrino Metabol 2: 146–159
PPARs in Human Physiology
Dec. 2001
PPAR-d: New Drug Target for Metabolic Syndrome?
Barish GD (RM Evans Lab) J Clin Invest. 2006. 116: 590–597. PPARδ: a
dagger in the heart of the metabolic syndrome
http://www.dnatube.com/video/579/Mouses-Running-Competition
PPAR-d: New Drug Target for Metabolic Syndrome?
http://www.dnatube.com/video/579/Mouses-Running-Competition