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Transcript
Steroid/Intracellular Receptor
Pharmacology

Therapeutic uses of agonist/antagonists

Replacement therapy
• adrenal steroids for Addison’s disease
• estrogen and progesterone for menopause
• thyroid (hypothyroid disorders)

Pharmacologic (non-physiological) uses
•
•
•
•

glucocorticoids as anti-inflammatory agents
estrogen/progesterone for contraception
androgens for increased muscle mass (abused by athletes)
mifepristone (RU486) for pregnancy termination
Cancer chemotherapy
• tamoxifen, anastrozole for breast cancer
• flutamide/bicalutamide, leuprolide for prostate cancer
AF2
AF1
a
b
LXR
FXR
PXR
CAR
oxysterols
farnesoids
zenobiotics
phenobarbital
Vitamin
D,are
thyroid
hormone,
Classical Steroid Hormone Receptors:
these
a small
subset
Retinoic
Acid members
Receptorsfound
of the 48 Nuclear/Intracellular Receptor
Family
& Adopted Orphan Receptors
in the human genome.
There are two genes coding for estrogen receptors in the
human genome: ERa and ERb
homology
18%
97%
60%
(there appears to be no AF-1 function in human ERb)
They bind the same DNA sequences, dimerize with themselves
and each other. Are they just redundant or do they have specific
physiological roles?
Expression patterns of ERs
• ERa
• ERb
–
–
–
–
–
–
–
–
–
–
breast
uterus
cervix
vagina
brain regions
Knockout phenotype:
female sterility, no mammary
gland development, obesity,
male sterility,
epididymal dysfunction,
testicular degeneration
ovary
prostate, testis
spleen, thymus
lung
hypothalamus, other
brain regions
Knockout phenotype:
male--fertile, female--reduced
fertility, ovarian dysfunction,
vascular problems/develop
hypertension as they age
Structure of the DNA binding domain
antagonists or partial agonists
agonists
The classic view of estrogen action: E binds to ER (displaces
a complex of chaperone proteins), ER forms dimers and interacts
with the ERE to activate genes by recruitment of co-activators.
How does estrogen act in classical mode to induce gene
expression from genes that have EREs in their promoter?
However, a number of observations
do not fit this model
 some genes induced by E do not have a recognizable ERE
 tamoxifen can inhibit E induction of genes in breast but can
be stimulatory of E responsive genes in uterus
 some of the effects of E are too fast to be transcriptional
(e.g. rapid activation of the MAP kinase pathway in <5 min.)
 pharmacological actions of agonists and antagonists do not
make sense in the classical model
new observation: ER does not need to bind to an ERE in
order to induce gene expression. Induction can occur
when ER binds indirectly to other transcription factors
such AP1 and then recruits coactivators.
classic pathway
(fos/jun)
indirect gene activation
pathway
The regulation of ERE versus AP1-activated promoters
depends on the receptor subtype, the ligand, and the cell type
ERa
E
TAM
Promoter
ERE
AP1
luciferase
luciferase
ERb
E
TAM
A Structural basis for the differences in ER activity when
agonist or antagonist ligands are bound
the C-terminal transactivation helix (H12)
is in green
AF2
Steroid Receptors also signal through
non nuclear mechanisms to activate MAP kinase
Summary and prospects for the future
1. estrogen receptor ligands can act through multiple mechanisms:
(1) classical ligand dependent induction thru an ERE
(2) indirect ligand dependent induction by interaction with AP1
or perhaps other DNA bound transcription factors.
(3) ligand-dependent interactions with Src kinase in the
cytoplasm and the activation of Map kinase signaling
2. ligands can have agonist or antagonist properties depending on
whether the receptor is ERa or ERb and the tissue complement
of co-regulators
3. the complexity of biological responses can be utilized
pharmacologically by the design of SERMs (selective estrogen
receptor modulators --other nuclear receptors such as AR, GR
may also be approached this way.
genistein: a
phytoestrogen
that is a selective
estrogen receptor
modulator (SERM):
every morning with
breakfast!
Results from the 2002 Women’s Health Initiative Study on
Hormone Replacement Therapy in Postmenopausal Women
WHI subject profile
note:
many subjects had been
E deficient for 10 yrs
 high percentage were
overweight.
Conjugated equine
estrogen (a mixture of
estrogens from pregnant
horse urine) and
medroxyprogesterone
were given orally--the
liver sees highest conc.
Corticosteroid Receptors
AF2
AF1
a
b
cortisol binds to both GR and MR
LXR
FXR
PXR
CAR
oxysterols
farnesoids
zenobiotics
phenobarbital
D, thyroid hormone,
aldosterone specific for MRVitamin
(mineralcorticoid
Retinoic Acid Receptors
receptor)
& Adopted Orphan Receptors
Therapeutic use of adrenal
steroids
1) Replacement therapy
Addison’s disease: administer a glucocorticoid (e.g. cortisol)
and a mineralocorticoid (e.g. fludrocortisone)
Congenital adrenal hyperplasia
21 b-hydroxylase deficiency is the most common cause
2) Diagnosis of Cushing’s syndrome
3) Cancer chemotherapy (especially lymphoma/leukemia)
4) Anti-inflammatory agents
The HPA axis regulates
the immune system, the
musculoskeletal system
and many tissues involved
in overall metabolism like
liver and fat.
Physiological effects of glucocorticoids
Metabolic
gluconeogenesis (liver)
release of amino acids (muscle)
release of fatty acids-lipolysis (fat)
plasma glucose
insulin secretion (pancreas-in response to glucose)
glucose uptake (muscle)
bone resorption
fibroblast proliferation
collagen synthesis
changes in mood and excitability
altered leukocyte functions (anti-inflammatory)
Glucocorticoid anti-inflammatory
mechanisms
 leukocyte
traffic control
 leukocyte function
 inhibition of the
prostaglandin/leukotriene pathway
GC
REC
GC
GC blocks NF-kB function and may also induce
inhibitors of the NF-kB pathway like IkB
Glucocorticoids block neutrophil migration out of blood
vessels by inhibiting response to chemotactic molecules
and by preventing passage of neutrophils through
endothelial gap junctions
Glucocorticoids inhibit
macrophage-Tcell
interactions by
blocking interleukin
induction and
preventing macrophage
activation
Glucocorticoids inhibit
tissue destruction by
macrophage by blocking
both macrophage
activation and subsequent
release of proteases like
collagenase, elastase, and
plasminogen activator
Toxic effects of chronic glucocorticoids
gluconeogenesis (liver)--hyperglycemia
release of amino acids-catabolism (muscle)--muscle weakness
release of fatty acids-lipolysis (fat)--together with increase in
insulin, leads to inappropriate fat deposition, obesity
insulin secretion (pancreas-in response to glucose)
hyperinsulinemia
bone resorption--leading to osteoporosis, fractures
fibroblast proliferation--thin skin, bruising, poor wound healing
collagen synthesis
growth retardation (in children)
changes in mood and excitability--euphoria, restlessness
altered leukocyte functions (anti-inflammatory)--may
mask underlying symptoms
suppression of the HPA axis: acute withdrawl can lead to death
Other members of the nuclear receptor family
AF2
AF1
a
b
LXR and FXR: regulate cholesterol
and bile acid homeostasis
PXR regulates drug metabolic
(cyp)genes
LXR
FXR
PXR
CAR
oxysterols
farnesoids
zenobiotics
phenobarbital