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

1218 to the nucleus. There, it interacts with specific DNA sequences within
the regulatory regions of affected genes. The short DNA sequences
that are recognized by the activated GR are called glucocorticoid
responsive elements (GREs) and provide specificity to the induction
of gene transcription by glucocorticoids. The consensus GRE
sequence is an imperfect palindrome (GGTACAnnnTGTTCT, where
n is any nucleotide) to which the GR binds as a receptor dimer. The
mechanisms by which GR activates transcription are complex and
not completely understood, but they involve the interaction of the GR
with transcriptional coactivators and with proteins that make up the
basal transcription apparatus. Genes that are negatively regulated by
glucocorticoids also have been identified. One well-characterized
example is the pro-opiomelanocortin gene. In this case, the GR
appears to inhibit transcription by a direct interaction with a GRE in
the POMC promoter, thereby contributing to the negative feedback
regulation of the HPA axis. Other genes negatively regulated by glucocorticoids
include genes for cyclooxygenase-2 (COX-2), inducible
nitric oxide synthase (NOS2), and inflammatory cytokines.
In some cases, the inhibitory effects of glucocorticoids on
gene expression have been linked to protein–protein interactions
between the GR and other transcription factors rather than to negative
effects of the GR at specific GREs. Indeed, protein–protein interactions
have been observed between the GR and the transcription
factors NF-κB and AP-1, which regulate the expression of a number
of components of the immune system (De Bosscher et al., 2003).
Such interactions repress the expression of genes encoding a number
of cytokines—regulatory molecules that play key roles in the
immune and inflammatory networks—and enzymes, such as collagenase
and stromelysin, that are proposed to play key roles in the
joint destruction seen in inflammatory arthritis. Thus, these
protein–protein interactions and their consequent negative effects on
gene expression appear to contribute significantly to the antiinflammatory
and immunosuppressive effects of the glucocorticoids.
The recognition that the metabolic effects of glucocorticoids
generally are mediated by transcriptional activation, whereas the
anti-inflammatory effects largely are mediated by transrepression,
suggests that selective GR ligands may maintain the anti-inflammatory
actions while lessening the metabolic side effects (McMaster and
Ray, 2008). Recent reports describing steroidal and nonsteroidal
compounds that exhibit anti-inflammatory actions but have little
effect on blood glucose suggest that such selective glucocorticoid
agonists may emerge from ongoing research.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Regulation of Gene Expression by Mineralocorticoids. Like the GR,
the MR also is a ligand-activated transcription factor and binds to
a very similar, if not identical, hormone-responsive element.
Although its actions have been studied in less detail than the GR,
the basic principles of action appear to be similar; in particular, the
MR also associates with HSP90 and activates the transcription of
discrete sets of genes within target tissues. Studies have not yet
identified differences in the DNA recognition motifs for the GR
and the MR that would explain their differential capacities to activate
discrete sets of target genes. The GR and MR differ in their
ability to inhibit AP-1–mediated gene activation, suggesting that
differential interactions with other transcription factors may
underlie their distinct effects on cell function. The MR has a
restricted expression: it is expressed in epithelial tissues involved
in electrolyte transport (i.e., the kidney, colon, salivary glands,
and sweat glands) and in nonepithelial tissues (e.g., hippocampus,
heart, vasculature and adipose tissue) where its functions are less
well understood.
Aldosterone exerts its effects on Na + and K + homeostasis primarily
via its actions on the principal cells of the distal renal tubules
and collecting ducts, whereas the effects on H + secretion largely are
exerted in the intercalated cells. The binding of aldosterone to the
MR in the kidney initiates a sequence of events that includes the
rapid induction of serum- and glucocorticoid-regulated kinase,
which in turn phosphorylates and activates amiloride-sensitive
epithelial Na + channels in the apical membrane. Thereafter,
increased Na + influx stimulates the Na + , K + -ATPase in the basolateral
membrane. In addition to these rapid genomic actions, aldosterone
also increases the synthesis of the individual components of
these membrane proteins as part of a more delayed effect.
Receptor-Independent Mechanism for Corticosteroid Specificity. The
availability of cloned genes encoding the GR and MR led to the surprising
finding that aldosterone (a classic mineralocorticoid) and cortisol
(generally viewed as predominantly glucocorticoid) bind the
MR with equal affinity. This raised the question of how the apparent
specificity of the MR for aldosterone was maintained in the face of
much higher circulating levels of glucocorticoids. We now know that
the type 2 isozyme of 11β-hydroxysteroid dehydrogenase
(11βHSD2) plays a key role in corticosteroid specificity, particularly
in the kidney, colon, and salivary glands (Hammer and Stewart,
2006). This enzyme metabolizes glucocorticoids such as cortisol to
receptor-inactive 11-keto derivatives such as cortisone (Figure 42–6).
Because its predominant form in physiological settings is the
hemiacetal derivative (Figure 42–7), which is resistant to 11βHSD
action, aldosterone escapes this inactivation and maintains mineralocorticoid
activity. In the absence of 11βHSD2, as occurs in an
inherited disease called the syndrome of apparent mineralocorticoid
excess, the MR is activated by cortisol, leading to severe
hypokalemia and mineralocorticoid-related hypertension. A state of
mineralocorticoid excess also can be induced by inhibiting 11βHSD
HO
11
C
Cortisol
Active
(binds to MR and GR)
11β-HSD2
11β-HSD1
O
11
Cortisone
Inactive
(binds to neither MR nor GR)
Figure 42–6. Receptor-independent mechanism by which 11βhydroxysteroid
dehydrogenase confers specificity of corticosteroid
action. Type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2)
converts cortisol, which binds to both the mineralocorticoid receptor
(MR) and the glucocorticoid receptor (GR), to cortisone, which
binds to neither MR nor GR, thereby protecting the MR from the
high circulating concentrations of cortisol. This inactivation allows
specific responses to aldosterone in sites such as the distal nephron.
The type 1 isozyme of 11β-HSD (11β-HSD1) catalyzes the reverse
reaction, which converts inactive cortisone to active cortisol in such
tissues as liver and fat. Only ring C of the corticosteroid is depicted;
see Figure 42–7 for complete structure.