Glucocorticoids Biochemistry Notes

COURSE CODE: 203 Pre-requisite: 109 Ms. ALMINA/Ms. RABIA SEMESTER: 3 BIOCHEMISTRY & GENETICS (III) REFERENCE TEXT BOOK: Lippincott’s illustrated review of biochemistry by pamela C. Champe and richard A. Harvey latest ed. STEROID HORMONES: GLUCOCORTICOIDS ...

COURSE CODE: 203 Pre-requisite: 109 Ms. ALMINA/Ms. RABIA SEMESTER: 3 BIOCHEMISTRY & GENETICS (III) REFERENCE TEXT BOOK: Lippincott’s illustrated review of biochemistry by pamela C. Champe and richard A. Harvey latest ed. STEROID HORMONES: GLUCOCORTICOIDS  Steroid hormones Cholesterol is the precursor of all classes of steroid hormones Glucocorticoids Mineralocorticoids Sex hormones  Glucocorticoids Glucocorticoids act mainly on glucose metabolism. They also regulate the metabolism of fats, proteins and water.  Glucocorticoids are: 1. Cortisol 2. Corticosterone 3. Cortisone  Glucocorticoids 1. Cortisol (very potent, accounts for about 95% of all glucocorticoid activity) 2. Corticosterone (provides about 4% of total glucocorticoid activity, but much less potent than cortisol) 3. Cortisone (almost as potent as cortisol) 1. Prednisone (synthetic, four times as potent as cortisol) 2. Methylprednisone (synthetic, five times as potent as cortisol) 3. Dexamethasone (synthetic, 30 times as potent as cortisol)  Chemistry and Half-life – Glucocorticoids are C21 steroids having 21 carbon atoms. – Half-life: Cortisol 70 to 90 minutes Corticosterone 50 minutes Cortisone Not Known  Synthesis of steroid hormones Synthesis involves shortening the hydrocarbon chain of cholesterol, and hydroxylation of the steroid nucleus The initial and rate-limiting reaction converts cholesterol to the 21-carbon pregnenolone  Enzymes Cholesterol side-chain cleavage enzyme complex (desmolase) Cytochrome oxidase of the inner mitochondrial membrane  Conti…. NADPH Molecular oxygen  Pregnenolone Parent compound for all steroid hormones Pregnenolone is oxidized and then isomerized to progesterone which is further modified to the other steroid hormones by hydroxylation reactions that occur in the ER and mitochondria.  Synthesis of Glucocorticoid  Secretion of adrenal cortical steroid hormones Steroid hormones are secreted on demand from their tissues of origin in response to hormonal signals. The corticosteroids and androgens are made in different regions of the adrenal cortex, and are secreted into blood in response to different signals.  Cortisol It is controlled by the hypothalamus, to which the pituitary gland is attached In response to severe stress (for example, infection), corticotropin-releasing hormone (CRH), produced by the hypothalamus, travels through capillaries to the anterior lobe of the pituitary  Conti…. Induces the production and secretion Of adrenocorticotropic hormone (ACTH). The polypeptide ACTH, the “stress hormone,” stimulates the adrenal cortex to synthesize and secrete the glucocorticoid cortisol  Activity of cortisol Cortisol allows the body to respond to stress through its effects on intermediary metabolism For example: Increased gluconeogenesis Inflammatory and immune responses  Negative affect As cortisol levels rise, the release of CRH and ACTH is inhibited.  Mechanism of steroid hormone action Each steroid hormone diffuses across the plasma membrane of its target cell and binds to a specific cytosolic or nuclear receptor These receptor–ligand complexes accumulate in the nucleus, dimerize, and bind to specific regulatory DNA sequences (hormone response elements, HRE)  An HRE is found in the promoter (or an enhancer element) for genes that respond to a specific steroid hormone, thus ensuring coordinated regulation of these genes.  Superfamily Receptors of: Steroid hormones Thyroid hormones Vitamin D Retinoic acid  Further metabolism of steroid hormones Steroid hormones are generally converted into inactive metabolic excretion products in the liver. Reactions include reduction of unsaturated bonds and the introduction of additional hydroxyl groups.  The resulting structures are made more soluble by conjugation with glucuronic acid or sulfate. Approximately 20–30% of these metabolites are secreted into the bile and then excreted in the feces, Whereas the remainder are released into the blood and filtered from the plasma in the kidney, passing into the urine  Functions Of Glucocorticoids – Glucocorticoids have metabolic effects on carbohydrates, proteins, fats and water. – These hormones also show mild mineralocorticoid effect.  On Carbohydrate Metabolism Glucocorticoids increase the blood glucose level by two ways 1. By promoting gluconeogenesis in liver from amino acids 2. By inhibiting the uptake and utilization of glucose by peripheral cells  Hypersecretion of glucocorticoids Increases the blood glucose level, resulting in hyperglycemia, glucosuria (is the excretion of glucose into the urine) and adrenal diabetes. Hyposecretion of these hormones – causes hypoglycemia and fasting during adrenal insufficiency will be fatal. – It decreases blood glucose level to a great extent, resulting in death  Protein Metabolism – Glucocorticoids promote the catabolism of proteins, leading to: 1. Decrease in cellular proteins 2. Increase in plasma level of amino acids 3. Increase in protein content in liver.  In hypersecretion of glucocorticoids, there is excess catabolism of proteins, resulting in muscular wasting and negative nitrogen balance.  Fat metabolism Glucocorticoids cause mobilization and redistribution of fats.  Actions on fats Mobilization of fatty acids from adipose tissue Increasing the concentration of fatty acids in blood Increasing the utilization of fat for energy.  At the same time, these hormones mobilize fats and make the fatty acids available for utilization, by which energy is liberated  Hypersecretion of glucocorticoids causes an abnormal type of obesity by increasing the deposition of fat in certain areas such as abdomen, chest, face and buttocks.  On Water Metabolism – Glucocorticoids play an important role in the maintenance of water balance, by accelerating excretion of water. – The adrenal insufficiency causes water retention.  Mineral Metabolism Glucocorticoids enhance the retention of sodium and to lesser extent, increase the excretion of potassium. Thus, hypersecretion of glucocorticoids causes edema, hypertension, hypokalemia and muscular weakness.  Bone – Glucocorticoids stimulate the bone resorption (osteoclastic activity) and inhibit bone formation and mineralization (osteoblastic activity). – So, in hypersecretion of glucocorticoids, osteoporosis occurs.  Glucocorticoids decrease the blood calcium by inhibiting its absorption from intestine and increasing the excretion through urine  Glucocorticoids enhance the resistance by the following ways: 1. Immediate release and transport of amino acids from tissues to liver cells for the synthesis of new proteins and other substances, which are essential to withstand the stress 2. Release of fatty acids from cells for the production of more energy during stress 3. Enhancement of vascular response to catecholamines and fatty acid-mobilizing action of catecholamines, which are necessary to withstand the stress  Glucocorticoids prevent the inflammatory reactions Inhibiting the release of chemical substances from damaged tissues by stabalizing the membrane of lysosomes, and thereby preventing vasodilatation and erythema in the affected area Causing vasoconstriction through the permissive action on catecholamines. ▪ This also prevents rushing of blood to the injured area. ▪ Decreasing the permeability of capillaries and preventing loss of fluid from plasma into the affected tissue. ▪ Inhibiting the migration of leukocytes into the affected area. ▪ Suppressing T cells and other leukocytes, so that there is reduction in the reactions of tissues which enhance the inflammatory process  Other (Nonadrenal) actions of ACTH 1. Melanocyte-stimulating effect. Because of structural similarity with melanocyte- stimulating hormone (MSH), ACTH shows melanocyte- stimulating effect. 2. It causes darkening of skin by acting on melanophores, which are the cutaneous pigment cells containing melanin. Diseases  β-HYDROXYSTEROID DEHYDROGENASE DEFICIENCY Virtually no glucocorticoids, mineralocorticoids, active androgens, or estrogens.  17-α-HYDROXYLASE DEFICIENCY Virtually no sex hormones or cortisol are produced. Increased production of mineralocorticoids causes sodium and fluid retention and, therefore, hypertension  Addison disease Autoimmune destruction of the adrenal cortex, is characterized by adrenocortical insufficiency  Cushing’s Syndrome Hypercortisolism Can be caused by pituitary or adrenal tumors Symptoms include central obesity but thin limbs; rounded face; weak bones; weak muscles; high blood pressure; high blood glucose; fragile skin; mood swings… THANK YOU