DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

both coagulation and fibrinolytic pathways, and imbalance in these
two opposing activities may cause adverse effects.
Estrogen Receptors
Estrogens exert their effects by interaction with receptors
that are members of the superfamily of nuclear
receptors. The two estrogen receptor genes are located
on separate chromosomes: ESR1 encodes ERα, and
ESR2 encodes ERβ. Both ERs are estrogen-dependent
nuclear transcription factors that have different tissue
distributions and transcriptional regulatory effects on a
wide number of target genes (reviewed by Hanstein et al.,
2004). Ligands that discriminate between ERα and
ERβ have been developed (Harrington et al., 2003) but
are not yet in clinical use. Both ERα and ERβ exist as
multiple mRNA isoforms due to differential promoter
use and alternative splicing (reviewed by Kos et al.,
2001; Lewandowski et al., 2002). The two human ERs
are 44% identical in overall amino acid sequence and
share the domain structure common to members of this
family. The estrogen receptor is divided into six functional
domains: The NH 2
-terminal A/B domain contains
the activation function-1 (AF-1) segment, which can
activate transcription independently of ligand; the
highly conserved C domain comprises the DNA-binding
domain, which contains four cysteines arranged in two
zinc fingers; the D domain, frequently called the “hinge
region,” contains the nuclear localization signal; and the
E/F domain has multiple functions, including ligand
binding, dimerization, and ligand-dependent transactivation,
mediated by the AF-2 domain. There are significant
differences between the two receptor isoforms in
the ligand-binding domains and in both transactivation
domains. Human ERβ does not appear to contain a
functional AF-1 domain. The receptors appear to have
different biological functions and respond differently
to various estrogenic compounds (Kuiper et al., 1997).
However, their high homology in the DNA-binding
domains suggests that both receptors recognize similar
DNA sequences and hence regulate many of the same
target genes.
ERα, the first discovered, is expressed most abundantly in the
female reproductive tract—especially the uterus, vagina, and
ovaries—as well as in the mammary gland, the hypothalamus,
endothelial cells, and vascular smooth muscle. ERβ is expressed most
highly in the prostate and ovaries, with lower expression in lung,
brain, bone, and vasculature. Many cells express both ERα and ERβ,
which can form either homo- or heterodimers. Both forms of ER are
expressed on breast cancers, although ERα is believed to be the predominant
form responsible for growth regulation (Chapter 63).
When co-expressed with ERα, ERβ can inhibit ERα-mediated
transcriptional activation in many cases (Hall and McDonnell, 1999).
Polymorphic variants of ER have been identified, but attempts to correlate
specific polymorphisms with the frequency of breast cancer
(Han et al., 2003), bone mass (Kurabayashi et al., 2004), endometrial
cancer (Weiderpass et al., 2000), or cardiovascular disease
(Herrington and Howard, 2003) have led to contradictory results.
A cloned G protein-coupled receptor, GPR30, also appears
to interact with estrogens in some cell systems, and its participation
in the rapid effects of estrogen is an attractive idea. However, four
GPR30 knockout (KO) mice strains show inconsistent data with few
stress or developmental phenotypes, and there is no consistent overlap
of these models with ERα and ERβ KO phenotypes. There may
be interaction/cross-talk between membrane-associated ERα and
membrane-localized GPR30 in some cancer cells, but in vivo confirmation
is lacking (Levin, 2008; Olde et al. 2009).
Mechanism of Action
Both estrogen receptors (ERs) are ligand-activated transcription
factors that increase or decrease the transcription
of target genes (Figure 40–4). After entering the
cell by passive diffusion through the plasma membrane,
the hormone binds to an ER in the nucleus. In the
nucleus, the ER is present as an inactive monomer
bound to heat-shock protein 90 (HSP90), and upon
binding estrogen, a change in ER conformation dissociates
the heat-shock proteins and causes receptor
dimerization, which increases the affinity and the rate
of receptor binding to DNA (Cheskis et al., 1997).
Homodimers of ERα or ERβ and ER α/ERβ heterodimers
can be produced depending on the receptor
complement in a given cell. The concept of ligandmediated
changes in ER conformation is central to
understanding the mechanism of action of estrogen
agonists and antagonists. The ER dimer binds to estrogen
response elements (EREs), typically located in the
promoter region of target genes with the consensus
sequence GGTCANNNTGACC, but several similar
sequences can act as estrogen response elements in a
promoter-specific context. The type of ERE with which
ERs interact also regulates the three-dimensional structure
of the activated receptor (Hall et al., 2002).
The ER/DNA complex recruits a cascade of coactivator
and other proteins to the promoter region of
target genes (Figure 40–4B). Three families of proteins
interact with ERs. The first of these has the ability to
modify nucleosome structure either in an ATP-dependent
manner, like SWI/Snf, or by histone methyltransferase
(HMT) activity, as in proteins such as PRMT1. The second
family comprises the p160/SRC proteins and
includes SRC-1 (steroid-receptor co-activator 1), SRC-2,
and SRC-3. The third family includes p300/CBP (cyclic
AMP response-element binding protein), co-activators
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CHAPTER 40
ESTROGENS AND PROGESTINS