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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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Additional recombinant hormones now approved
Two additional recombinant hormones have recently gained marketing approval: thyroid-stimulating hormone and calcitonin.
346 BIOPHARMACEUTICALS
Figure 8.17. Structure of the iodine-containing amino acid-based thyroid hormones — thyroxine and triiodothyronine
Structurally, thyroid-stimulating hormone (TSH or thyrotrophin) is classified as a member of the gonadotrophin family, although functionally it targets the thyroid gland as opposed to the gonads. As with other gonadotrophins, it is a heterodimeric glycoprotein displaying a common a-subunit and a unique b-subunit. The b-subunit shows less homology to that of other members of the group. It consists of 118 amino acids, is particularly rich in cysteine residues and contains one N-linked glycosylation site (Asn 23).
TSH is synthesized by a distinct pituitary cell type; the thyrotroph. Its synthesis and release is promoted by thyrotrophin releasing hormone (TRH, a hypothalamic tripeptide hormone). TSH exerts its characteristic effects by binding specific receptors found primarily, but not exclusively, on the surface of thyroid gland cells. Binding to the receptor activates adenylate cyclase, leading to increased intracellular cAMP levels. Ultimately, this triggers TSH’s characteristic effects on thyroid function, including promoting iodine uptake from the blood, synthesis of the iodine-containing thyroid hormones, thyroxine (T4) and triiodothyronine (T3) (Figure 8.17) and release of these hormones into the blood, from where they regulate many aspects of general tissue metabolic activity. Elevated plasma levels of T4 and T3 also promote decreased TSH synthesis and release by a negative feedback mechanism.
TSH is approved for medical use as a diagnostic aid in the detection of thyroid cancer/thyroid remnants in post-thyroidectomy patients. Thyroid cancer is relatively rare, exhibiting the highest incidence in adults, particularly females. First-line treatment is surgical removal of all or most of the thyroid gland (thyroidectomy). This is followed by thyroid hormone suppression therapy, which entails administration of T3 or T4 at levels sufficient to maintain low seum TSH levels through the negative feedback mechanism mentioned earlier. TSH suppression is required
HORMONES OF THERAPEUTIC INTEREST 347
in order to prevent the TSH-mediated stimulation of remnant thyroid cancer cells. The recurrence of active thyroid cancer can be detected by administration of TSH along with radioactive iodine. TSH promotes uptake of radioactivity, which can then be detected by appropriate radio-imaging techniques.
The commercial recombinant TSH product (trade name, Thyrogen; international nonproprietary name; thyrotrophin-a) is produced in a CHO cell line co-transfected with plasmids harbouring the DNA sequences coding for the a- and b-TSH subunits. The cells are grown in batch harvest animal cell culture bioreactors. Following recovery and concentration (ultrafiltration), the TSH is chromatographically purified and formulated to a concentration of 0.9 mg/ml in phosphate buffer containing mannitol and sodium chloride as excipients. After sterile filtration and aseptic filling into glass vials, the product is freeze-dried. Finished product has been assigned a shelf-life of 3 years when stored at 2-8°C.
Calcitonin is a polypeptide hormone which (along with parathyroid hormone and the vitamin D derivative, 1,25-dihydroxycholecalciferol) plays a central role in regulating serum ionized calcium (Ca2+) and inorganic phosphate (P^ levels. The adult human body contains up to 2 kg of calcium, of which 98% is present in the skeleton (i.e. bone). Up to 85% of the 1kg of phosphorus present in the body is also found in the skeleton (the so-called mineral fraction of bone is largely composed of Ca3 (PO4)2 which acts as a body reservoir for both calcium and phosphorus). Calcium concentrations in human serum approximate to 0.1 mg/ml and are regulated very tightly (serum phosphate levels are more variable).
Calcitonin lowers serum Ca2+ and P, levels, primarily by inhibiting the process of bone resorption, but also by decreasing resorption of P, and Ca2+ in the kidney. Calcitonin receptors are predictably found primarily on bone cells (osteoclasts) and renal cells, and generation of cAMP via adenylate cyclase activation plays a prominent role in hormone signal transduction.
Calcitonin is used clinically to treat hypercalcaemia associated with some forms of malignancy and Paget’s disease. The latter condition is a chronic disorder of the skeleton in which bone grows abnormally in some regions. It is characterized by substantially increased bone turnover rates which reflects over-stimulation of both osteoclasts (promote bone resorption, i.e. degradation of old bone) and osteoblasts (promotes synthesis of new bone).
In most mammals, calcitonin is synthesized by specialized parafollicular cells in the thyroid. In sub-mammalian species, it is synthesized by specialized anatomical structures known as ultimobranchial bodies.
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