Page 720 - Basic _ Clinical Pharmacology ( PDFDrive )

706 SECTION VII Endocrine Drugs

21 21
CH OH CH OH
2
2
20 20
C O C O
H C 18 OH H C 18 OH
3
3
HO 12 17 HO 12 17
11 13 11 13 16
19 16 19
H C 14 H C H 14 15
3
3
1 9 8 15 1 9 8
2 10 10
2
H H
3 4 5 7 3 5 7
O 6 O 4 6
Cortisol (hydrocortisone) Prednisolone
21 21
CH OH CH OH
2
2
20 20 O CH
C O C O 3
H C 18 OH H C 18
3
3
HO 12 17 HO 12 17 C
11 13 11 13
19 16 CH 3 19 16 O CH 3
H C 14 H C 14
3
3
1 9 8 15 1 9 8 15
2 10 2 10
F F
3 5 7 3 5 7
O 4 6 O 4 6
Betamethasone Triamcinolone (acetonide moiety shaded)
FIGURE 39–3 Chemical structures of several glucocorticoids. The acetonide-substituted derivatives (eg, triamcinolone acetonide) have
increased surface activity and are useful in dermatology. Dexamethasone is identical to betamethasone except for the configuration of the
methyl group at C 16 : in betamethasone it is beta (projecting up from the plane of the rings); in dexamethasone it is alpha.
stochastic activities. In addition, rare mutations in hGR may for the hormone, the complement of transcription factors and
result in partial glucocorticoid resistance. Affected individuals coregulators, and post-transcription events determine the relative
have increased ACTH secretion because of reduced pituitary feed- specificity of these hormones’ actions in various cells. The effects
back and additional endocrine abnormalities (see below). of glucocorticoids are mainly due to proteins synthesized from
The prototype GR isoform is composed of about 800 amino acids mRNA transcribed from their target genes.
and can be divided into three functional domains (see Figure 2–6). Some of the effects of glucocorticoids can be attributed to
The glucocorticoid-binding domain is located at the carboxyl their binding to mineralocorticoid receptors. Indeed, MRs bind
terminal of the molecule. The DNA-binding domain is located in the aldosterone and cortisol with similar affinity. A mineralocor-
middle of the protein and contains nine cysteine residues. This region ticoid effect of the higher levels of cortisol is avoided in some
folds into a “two-finger” structure stabilized by zinc ions connected to tissues (eg, kidney, colon, salivary glands) by expression of
cysteines to form two tetrahedrons. This part of the molecule binds 11β-hydroxysteroid dehydrogenase type 2, the enzyme responsible
to the GREs that regulate glucocorticoid action on glucocorticoid- for biotransformation to its 11-keto derivative (cortisone), which
regulated genes. The zinc fingers represent the basic structure by has minimal action on aldosterone receptors.
which the DNA-binding domain recognizes specific nucleic acid The GR also interacts with other regulators of cell function.
sequences. The amino-terminal domain is involved in the transactiva- One such molecule is CLOCK/BMAL-1, a transcription factor
tion activity of the receptor and increases its specificity. dimer expressed in all tissues and generating the circadian rhythm
The interaction of glucocorticoid receptors with GREs or of cortisol secretion (Figure 39–2) at the suprachiasmatic nucleus
other transcription factors is facilitated or inhibited by several of the hypothalamus. CLOCK is an acetyltransferase that acety-
families of proteins called steroid receptor coregulators, divided lates the hinge region of the GR, neutralizing its transcriptional
into coactivators and corepressors. The coregulators do this by serv- activity and thus rendering target tissues resistant to glucocorti-
ing as bridges between the receptors and other nuclear proteins coids. As shown in Figure 39–2, lower panel, the glucocorticoid
and by expressing enzymatic activities such as histone acetylase or target tissue sensitivity rhythm generated is in reverse phase to that
deacetylase, which alter the conformation of nucleosomes and the of circulating cortisol concentrations, explaining the increased
transcribability of genes. sensitivity of the organism to evening administration of glucocor-
Between 10% and 20% of expressed genes in a cell are regu- ticoids. The GR also interacts with NF-κB, a regulator of produc-
lated by glucocorticoids. The number and affinity of receptors tion of cytokines and other molecules involved in inflammation.