Info

*S, short (i.e., t1/2 = 8-12 h; I, intermediate (i.e., t1/2 = 12-36 h); L, long (i.e., t1/2 = 36-72 h).

^These dose relationships apply only to oral or intravenous administration, as glucocorticoid potencies may differ greatly following intramuscular or intraarticular administration. ¿This agent is not used for glucocorticoid effects.

*S, short (i.e., t1/2 = 8-12 h; I, intermediate (i.e., t1/2 = 12-36 h); L, long (i.e., t1/2 = 36-72 h).

^These dose relationships apply only to oral or intravenous administration, as glucocorticoid potencies may differ greatly following intramuscular or intraarticular administration. ¿This agent is not used for glucocorticoid effects.

genes, thereby changing the levels and array of proteins synthesized by the various target tissues. As a consequence of the time required to effect these changes, most effects of corticosteroids are not immediate but become apparent after several hours. This fact is of clinical significance, because a delay generally is seen before beneficial effects of corticosteroid therapy become manifest. Although corticosteroids predominantly act to increase expression of target genes, there are well-documented examples in which glucocorticoids decrease transcription. In addition to these genomic effects, some immediate actions of corticosteroids may be mediated by membrane-bound receptors.

Regulation of Gene Expression by Glucocorticoids

The GR resides predominantly in the cytoplasm in an inactive form until it binds glucocorticoids. The inactive GR is complexed with other proteins, including heat-shock proteins and an immunophilin. After ligand binding, the GR dissociates from its associated proteins and translocates to the nucleus. There, it interacts with specific DNA sequences called glucocorticoid responsive elements (GREs) within the regulatory regions of affected genes. These GREs thus provide specificity to the regulation of gene transcription by glucocorticoids.

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. The selective actions of GR and MR are thought to result from interactions with other transcription factors that also are recruited to the promoter regions of target genes as well as from the restricted pattern of expression of the MR. Unlike the GR, which has a more ubiquitous distribution, the MR is expressed principally in the kidney (distal cortical tubule and cortical collecting duct), colon, salivary glands, sweat glands, and hippocampus.

Receptor-Independent Mechanism for Corticosteroid Specificity

Biochemical studies of the GR and MR led to the surprising finding that aldosterone (a classic mineralocorticoid) and cortisol (predominantly a 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 cortisol. We now know that the type 2 isozyme of 11 fi-hydroxysteroid dehydrogenase (11fiHSD2) plays a key role in corticosteroid specificity, particularly in the kidney, colon, and salivary glands. This enzyme metabolizes glucocorticoids such as cortisol to receptor-inactive 11-keto derivatives such as cortisone (Figure 59-4) and thus forms an enzymatic barrier that prevents cortisol from reaching the MR. Because its predominant form in physiological settings is the hemiacetal derivative (Figure 59-4), aldosterone is resistant to this inactivation and maintains mineralocorticoid activity.

Cortisone

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