Enzymes glucocorticoid effect

As pointed out above, nt1 receptors have been discovered in lymphoma cells selected for resistance to the cytolytic glucocorticoid effect. Since receptors from which the M domain had been eliminated by cDNA manipulation still function to some extent in transfection studies it was important to find out whether nt1 receptors would also be able to mediate some hormonal response. This was in fact observed when nt lymphoma variants were transfected with a DNA construct consisting of the LTR region of the mouse mammary tumour virus coupled to the gene for chloramphenicol acetyltransferase (U. Gehring and H. Losert, unpublished experiments). Hormonal induction of enzyme activity was consistently observed but was low, as one might expect. 

Because of their enzyme-inducing effects, barbiturates can cause increased inactivation of other compounds (anticoagulants, phenytoin, theophylline, digoxin, glucocorticoids, etc.). This may lead to serious problems with drug interactions. 

Besides the mineralcorticoid effect on the electrolyte metabolism, the adrenocortical hormones also influence the metabolism of glucose by promoting glycogen formation in the liver, especially from protein. This effect is termed the glucocorticoid effect and is manifested especially by the 11/3-hydroxy compounds. Emphasizing the breakdown of protein, this effect is also called the catabolic effect. The mechanism of this hormone action seems to involve the de novo formation of more enzymes of amino acid metabolism, e.g., tyrosine a-ketoglutarate transaminase, tr5rptophan pyrrolase, etc. (cf. Enzyme Induction, Chapt. VII-7). 

Such a medical adrenalectomy is an efficacious treatment for metastatic breast and prostate cancer, since it diminishes the levels of circulating sex hormones. Glucocorticoids are administered concomitantly to suppress enhanced corticotrophin release. Cortisol is preferable to dexamethasone in this situation because aminoglutethimide markedly enhances the hepatic microsomal metabolism of dexamethasone. Hepatic enzyme induction may be responsible for the development of tolerance to the side effects of aminoglutethimide, such as ataxia, lethargy, dizziness, and rashes. 

Mechanism of Action A long-acting glucocorticoid that inhibits accumulation of inflammatory cells at inflammation sites, phagocytosis, lysosomal enzyme release and synthesis, and releaseof mediators of inflammation. Therapeutic Effect Prevents and suppresses cell and tissue immune reactions and inflammatory process. Pharmacohinetics Rapidly, completely absorbed from the G1 tract after oral administration. Widely distributed. Protein binding High. Metabolized in the liver. Primarily excreted in urine. Minimally removed by hemodialysis. Half-life 3-4.5 hr. 

Most of the established pharmacological effects of glucocorticoids are mediated by cytoplasmic glucocorticoid receptors. After binding to the receptor, the steroid-receptor complex binds to chromatin and stimulate the formation of mRNA. The mRNA stimulates the synthesis of enzymes which produce various pharmacological actions. 

Some of the effects of glucocorticoids can be attributed to their binding to aldosterone receptors (ARs). Indeed, ARs bind aldosterone and cortisol with similar affinity. A mineralocorticoid effect of cortisol is avoided in some tissues by expression of llE>-hydroxysteroid dehydrogenase type 2, the enzyme responsible for biotransformation to its 11-keto derivative (cortisone), which has minimal affinity for aldosterone receptors. 

Rifampicin and other drugs that induce liver enzymes increase the metabolism of glucocorticoids (497), sufficient to reduce their therapeutic effects, for example in asthma (498). 

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