Proposed Mechanism Of Steroid Action

While certain properties of glucocorticoid action are a result of direct posttranscriptional effects, most are a consequence of effects on gene expression. Steroids transported by transcortin enter the target cell by diffusion and then form a complex with its cytosolic receptor protein. Glucocorticoids bind to cytoplasmic glucocorti-coid receptors containing two subunits of the heat shock protein that belong to the 90-kDa family. The heat shock protein dissociates, allowing rapid nuclear translocation of the receptor-steroid complex. Within the nucleus, the glucocorticoid receptor induces gene transcription by binding to specific sequences on DNA called glucocorticoid response elements in the promoter-enhancer regions of responsive genes (Fig. 60.5). In certain cases, the glucocorticoid receptor can interact with nuclear factor-kB and AP-1 to inhibit gene expression activated by these proinflammatory transcription factors. Because their side effects are thought to be a consequence of gene induction, glucocorticoids that can repress inflammatory genes without inducing gene transcription are in development.

The pivotal role that the glucocorticoid receptor plays in hormone action is illustrated by the fact that the magnitude of induction of a regulatable gene and cellular responsiveness are directly proportional to the number of occupied receptors. A decrease in gluco-corticoid receptor number (down-regulation) produced by protein degradation may be responsible for the increase in steroid resistance observed clinically. Down-regulation of glucocorticoid receptors also is a potential mechanism for terminating glucocorticoid-dependent responses and for curtailing excessive cell stimulation when circulating levels of steroids are high. The effectiveness of glucocorticoids will also be compromised by the concomitant administration of other drugs that enhance the clearance of glucocorticoids (ephedrine, phenytoin, rifampin). Glucocorticoids, which bind to mineralocorticoid receptors in the kidney to regulate salt balance, are inactivated by l1-p-hydroxysteroid re-ductase so that they do not elicit mineralocorticoid

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