Effects of cortisol and corticosteroids
Corticosteroids, cortisol and synthetic derivatives such as prednisone, prednisolone, dexamethasone, betamethasone, act primarily at the nuclear level, they have genomic effects.
These molecules penetrate into the cytoplasm of the target cells, bind to a cytoplasmic protein receptor which changes conformation and the complex hormone-receptor thus formed penetrates into the nucleus where, in a dimeric association, it modulates the activity of glucocorticoid-response elements to increase or decrease transcriptions, i.e. the synthesis of mRNA and its corresponding proteins. Corticosteroids interact with their receptors when they are in a particular conformational state which exists when they are bound to hsp 90 and hsp 70 (heat shock protein).
The complex glucocorticoid-receptor formed in the cytoplasm also neutralizes Nuclear Factor-KB, NF-KB, which activates gene transcription for the synthesis of pro-inflammatoiry molecules (TNF-A, interleukins 1 and 2, cyclooxygenase 2) and of adherence factors, like ICAM (intercellular adhesion molecule).
Moreover, corticosteroids partly neutralize a heterodimeric protein called AP-1 (activator protein-1), formed of the proteins Fos and Jun, which activates the transcription of several genes implicated in the synthesis of pro-inflammatory proteins.
By these mechanisms, corticosteroids:
- increase the intracellular protein synthesis of lipocortin also called lipomoduline , classified among annexins, which inhibits A2 phospholipase, responsible for arachidonic acid release from membrane phospholipids. The decrease of free arachidonic acid reduces the synthesis of prostaglandins, thromboxanes, leukotrienes, and PAF, which explains at least partly their anti-inflammatory properties.
- decrease the synthesis of TNF (tumor necrosis factor), interleukin I, t-Pa (tissue plasminogen activator), cyclooxygenases, NO-synthases.
- increase the synthesis of metallothioneins, proteins rich in cysteine, present in organs such as liver, kidney and also the brain and which selectively binds metals like zinc and copper but whose biological role is not well understood.
- Increase the synthesis of various enzymes, tyrosine-amino-transferase, glutamine-synthetase and glycerophosphate-deshydrogenase, for example.
These molecular effects are responsible for their pharmacological properties known for a long time:
- Antiinflammatory effect
Corticosteroids reduce the clinical symptoms (edema, redness, heat, pain) and biological (sedimentation rate, fibrinogen) of inflammation. They act both on the initial, vascular phase, and the late, cellular phase. They are used in the treatment of various rheumatic diseases.
- Anti-allergic effect
The anti-allergic effect of corticosteroids, at least partly the consequence of their anti-inflammatory effect, is clinically obvious. They are effective in the treatment of asthma, angioedema (acute laryngeal edema) of various cutaneous allergic symptoms.
- Immunosupressive effect
Without modifying antigen/antibody reactions themselves, corticosteroids, by their anti-inflammatory and leucocytic effects, decrease the reactions of rejection of grafted organs as well as the symptoms of various diseases with an immunological component such as lupus erythematosus, polyarteritis, dermatomyositis, scleroderma and subacute thyroiditis.
- Action on blood cells
Corticosteroids, by complex mechanisms, particularly redistribution between organs, decrease the number of eosinophils (Thorn test), T lymphocytes, monocytes, and increase that of neutrophils. They can moreover modify the activity of these cells.
- Action on the thymus
Corticosteroids cause the involution of the thymus. This involution could result from an apoptotic effect by DNA destruction. The mechanisms of apoptosis are unclear but could involve endonucleases and intracellular penetration of calcium. The cells contain mechanisms whose activation can lead to their death.
- Effects on carbohydrate, protein, lipid and electrolyte metabolism:
Corticosteroids have a hyperglycemic action (this is the reason for the term glucocorticoid) due to an increase in the production of glucose by glycogen formation at the expense of proteins, it is gluconeogenesis, and by decrease of glucose consumption by peripheral tissues. Surrenalectomy elicits a tendency to hypoglycemia and a great sensitivity to the effect of insulin. On the other hand the administration of corticosteroids induces the outbreak of a diabetes known as cortisonic, not very sensitive to insulin.
Corticosteroids increase protein catabolism and elicit muscle wasting with fatigability, osseous protein matrix alteration (osteoporosis). A food rich in proteins is advised during treatment by corticosteroids.
There is a redistribution of lipids. Corticosteroids mobilize lipids and redistribute them in a particular way with accumulation at the level of face and back.
- Water and Electrolytes Na/Ca:
Corticosteroids such as cortisol have a discrete but real mineralocorticoid action, inducing sodium and water retention and potassium leakage. Corticosteroids increase urinary elimination of phosphorus and calcium and decrease digestive absorption of calcium, which induces calcium deficiency. They increase bone resorption and slow down its formation