Biological functions and use of T4

T4 is the quantitatively major thyroid hormone (TH) secreted from the thyroid gland, but it is less potent than 3,30 ,5-triiodothyronine (T3) in many genomic actions of THs. Although T4 has been thought to be a prohormone of the active form T3, it turns out that T4 functions as a hormone.

Discovery 

Edward Calvin Kendall first isolated T4 in crystalline form in 1914.Charles Robert Harington determined its chemical formula in 1926,and synthesized it in 1927. 

Structure 

T4 has two iodine atoms in the phenolic ring and two in the tyrosyl ring. Properties molecular formula, C15H11I4NO4; Mr 776.87; physical state, white needle-like crystals, odorless, and tasteless; water solubility, 0.105mg/L at 25°C.

Synthesis and release Synthesis 

T4 and a small proportion of T3 are synthesized by the iodination of specific sites on tyrosine residues,subsequent oxidative coupling between the two iodotyrosines on 660 kDa thyroglobulin (TG) molecules at the luminal surface of the thyroid follicle cells, and then processing in lysosome to be released into the bloodstream. The daily production rate of T4 is 130 nmol/day/70 kg.

Biological functions 

Target cells/tissues and functions 

T4 is not elucidated whether T4, like T3, exerts TH actions through the signaling pathways of Types 1 and 2.The fig below shows T4 actions. T4 acts on actin polymerization via extranuclear TRΔα1 (Type 3 signaling) in rat cultured astrocytes resulting in altered cell attachment. T4 actions via plasma membrane TH receptor on the integrin αvβ3 (Type 4 signaling) are detected in mouse glioma (cell proliferation by MAPK) and chicken embryonic chorioallantoic membrane (angiogenesis by MAPK and bFGF2). 

T4 also acts on the inward flux of Na+ in rat neonatal myocardiocytes resulting in the activation of cell excitability and on membrane Ca²⁺-ATPase activity in human and rat erythrocytes.Although the action mechanisms have yet to be resolved, T4 injection into Rana catesbeiana tadpoles increases the activity of carbamyl phosphate synthetase 1 in the liver, where neither deiodinase 1 (dio1) nor deiodinase 3 (dio3) are expressed. Studies on the invertebrate thyroid system demonstrate that T4 exposure accelerates development to metamorphosis in tunicates and echinoderms, and strobilation in cnidarians.

Use for diagnosis and treatment 

Antithyroid medicine such as carbimazole (used in the United Kingdom), methimazole (used in the United States), propylthiouracil, and radioactive iodine are used in treatments for hyperthyroidism. Patients with hypothyroidism are treated with a synthetic long-acting form of T4 known as levothyroxine. Triac and D-T4 have been used as cholesterol- and lipid-lowering drugs.

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