Use and Biological functions of 3,3',5-Triiodo-L-thyronine

3,3',5-Triiodo-L-thyronine(T3) is an active form of thyroid hormone (TH), and it plays an important role in body control, including growth and development, metabolism, body temperature, and heart rate.

Discovery

Jack Gross and Rosalind Pitt-Rivers identified T3 in human plasma as a more active component than thyroxine (T4) in 1952.Rat liver deiodinase 1 was described as the first deiodinase enzyme for THs in 1976.

Structure

3,3',5-Triiodo-L-thyronine (T3) is a derivative of the amino acid tyrosine. T3 has one iodine atom in the phenolic ring and two in the tyrosyl ring. Properties Molecular formula, C15H12I3NO4; Mr 650.97; physical state, solid, odorless, and tasteless; water solubility, 3.96mg/L at 37°C.

Synthesis

Eighty percent of circulating T3 is generated from T4 by deiodinases 1 and 2 (DIO1 and DIO2) in peripheral tissues. These enzymes are selenocysteine-dependent membrane proteins. However, T4 is also converted to various metabolites besides T3 by specific enzymes,as shown in Fig. 121A.1. Daily production rates of T3 are 48 nmol/day/70 kg.

Biological functions

Phenotype in gene modified animals Mice lacking TRα1 have abnormal heart function and lower body temperature. Mice lacking both TRα1 and TRα2 have impaired postnatal development and decreased postnatal survival, whereas mice lacking the TRβ gene have mild dysfunction of the pituitary-thyroid axis as well as deficits in auditory function and eye development. Knock-in mice harboring a C-terminal frameshifted TRβ have dysfunction of the pituitary-thyroid axis and the nervous system, abnormal regulation of cholesterol, neurological growth retardation, hearing loss, and thyrotoxic skeletal phenotype.In an amphibian, transgenic Xenopus laevis overexpressing dominant negative TRα prevents coactivator recruitment. This affects the proliferation of the jaw and brain, resorption of the gills and tail, and remodeling of the intestinal tract.

Clinical implications

A close relationship is found between more than 347 family members with TH resistance (Refetoff syndrome) and 124 different mutations in the TRβ gene. Symptoms of this disorder are increased TH with nonsuppressible thyrotropin, goiter, short stature, decreased weight, tachycardia, hearing loss, attention deficit hyperactivity disorder, and dyslexia, but most patients are heterozygous and euthyroid. Mutant proteins act as a dominant negative form of TRβ. In contrast, there have been no reports on TRα mutation in humans.

Use for diagnosis and treatment

Patients with TH resistance are usually identified with elevated levels of free or total T4 and/or T3 in association with normal or slightly elevated thyrotropin.The most common cause is TRβ gene mutations. However, mutations in monocarboxylate transporter 8 responsible for T3 uptake and selenocysteine insertion sequence binding protein that is required for a translational step of selenium-containing deiodinase transcripts have also been associated with this condition. T3 mimetic eprotirome (KB2115) and sobetirome (GC-1) effectively decrease plasma low-density lipoprotein cholesterol and stimulate bile acid synthesis in humans.