The Glucocorticoids

The glucocorticoids mainly influence carbohydrate metabolism and, to a certain extent, protein and lipid metabolism. The main glucocorticoid is cortisol, with a daily secretion of 15 mg. Cortisol is synthesized through the 11-P-hydroxylation of 11-deoxycortisol. Besides cortisol, the adrenal 

The clinical manifestations of 11-p-hydroxylase deficiency are virilization, resulting from the overproduction of androgen, and hypertension, stemming from the overproduction of deoxycorticosteroids. 

The glucocorticoids work by binding to specific intracellular receptors in target tissues. The receptor hormone complex is then transported into the nucleus in which the complex interacts with the DNA, thus augmenting the synthesis of specific RNAs. 

Cortisol, corticosterone, aldosterone, and the synthetic steroids used in steroid therapy (e.g., prednisolone, dexamethasone, and triamcinolone) are glucocorticoid agonists and therefore elicit glucocorticoid responses. A number of other steroids bind to the glucocorticoid receptor and thus suppress glucocorticoid responses. 

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The uses of corticosteroid antiinflammatory dmgs in veterinary medicine are many and varied. In the intact animal, the glucocorticoids and mineralcorticoids are produced in the adrenal glands. Exogenous compounds are, therefore, used for their glucogenic physiologic effect in cases where the... 

Two zinc-containing motifs in the glucocorticoid receptor form one DNA-binding domain... 

Figure 10.11 Sequence-specific interactions between DNA (yellow) and the recognition helix (red) of the glucocorticoid receptor. Three residues, Lys 461, Val 462 and Arg 466 make specific contacts with the edges of the bases In the major groove.

The individual domains of the two receptors both have structures similar to that of the glucocorticoid receptor, and they bind to DNA in a similar way, with their recognition helices in the major groove. The dimer contacts are, however, totally different. In the glucocorticoid receptor, which binds to a palindromic DNA sequence like the 434 repressor described in Chapter 8, the domains interact symmetrically in a head-to-head fashion equivalent... 

Hard, T., et al. Solution structure of the glucocorticoid receptor DNA-binding domain. Science 249 157-160, 1990. 

Luisi, B.F., et al. Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. 

The discovery in 1954 that fluorination of the glucocorticoid hormone cortisol could bring about remarkable changes in the biological properties of the hormone was entirely unexpected and violated the then prevalent belief that synthetic variants could not surpass a naturally occurring hormone in its biological activity. Because of the impact that fluorination of steroids has had on subsequent developments in this area the history of the discovery of fluorocortisol will be briefly recounted. 

When in the late 1940 s the remarkable therapeutic effects of the glucocorticoids cortisone and hydrocortisone were discovered, new raw materials had to be developed to produce these complicated molecules, and new synthetic methods devised to convert either a 20-ketopregnane or 21-acetoxy-20-ketopregnane to the dihydroxyacetone side-chain characteristic of these corticoids. This latter challenge produced some extremely useful new organic chemical reactions, many of which have wider application outside of steroids. 

Storage and utilization of tissue glycogen, maintenance of blood glucose concentration, and other aspects of carbohydrate metabolism are meticulously regulated by hormones, including insulin, glucagon, epinephrine, and the glucocorticoids. 

Amongst the —> immunosuppressive agents besides the —> glucocorticoids the modern nontoxic drugs have become drugs of choice including ciclosporin, tacrolimus or ascomycin. 

There is a risk of acute renal failure when iodi-nated contrast material that is used for radiological studies is administered with metformin. Metformin therapy is stopped for 48 hours before and after radiological studies using iodinated material. Alcohol, amiloride, digoxin, morphine, procainamide, quini-dine, quinine ranitidine, triamterene, trimethoprim, vancomycin, cimetidine, and furosemide all increase the risk of hypoglycemia. There is an increased risk of lactic acidosis when metformin is administered with the glucocorticoids. 

Corticotropin (ACTH) is an anterior pituitary hormone that stimulates the adrenal cortex to produce and secrete adrenocortical hormones, primarily the glucocorticoids. 

Because ACTH stimulates the release of glucocorticoids from the adrenal gland, adverse reactions seen with the administration of this hormone are similar to those seen with the glucocorticoids (see Display 50-2) and affect many body systems. The most common adverse reactions include ... 

The adrenal gland lies on the superior surface of each kidney. It is a double organ composed of an outer cortex and an inner medulla In response to ACTH secreted by the anterior pituitary, the adrenal cortex secretes several hormones (the glucocorticoids, the mineralocorticoids, and small amounts of sex hormones). 

This section of the chapter discusses the hormones produced by the adrenal cortex or the adrenocortical hormones, which are the glucocorticoids and mineralocorticoids. These hormones are essential to life and influence many organs and structures of the body. The glucocorticoids and mineralocorticoids are collectively called corticosteroids. 

The glucocorticoids influence or regulate functions such as the immune response system, the regulation of glucose, fat and protein metabolism, and control of the anti-inflammatory response. Table 50-1 describes the activity of the glucocorticoids within the body. 

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