Thyroid hormones are iodinated derivatives of tyrosine that are synthesized in the follicular cells of the thyroid gland. The noniodinated thyronine can be regarded as the basic structure of these hormones (Fig. 1). 3,5,3′-Triiodothyronine (T3) is the major hormonally active derivative, whereas thyroxine (3,5,3′,5′-tetraiodothyronine, T4) has one-fifth of its biological activity. Biosynthesis of the hormones involves thyroglobulin, a tyrosine-rich protein stored in the follicle lumen. Iodine is oxidized to I2 by a pThyroid Hormones eroxidase of the follicular cells and then coupled covalently to tyrosine residues of thyroglobulin. The side chains of other tyrosine residues of thyroglobulin are subsequently coupled to the iodinated tyrosine residues, with the formation of diphenylether covalent bonds and completion of the basic thyronin structure. In this form, the thyroid hormones are still part of the thyroglobulin molecule. Under the stimulatory influence of thyrotropic hormone (TSH, thyrotropin), by way of a membrane receptor and activation of adenylyl cyclase (1), the iodinated thyroglobulin is taken up by the thyreocytes and degraded by proteolysis, and the freed T4 and T3 are released into the circulation. The bulk of T4 and T3 in the circulation is protein-bound. Only the free hormones can penetrate cells. In target cells, T4 is 5′-deiodinated to T3, which, at the cellular level, is the active hormone.
Figure 1. Structures of thyronine, T3, and T4.
Thyroid hormones exert a broad range of effects on cell growth, development, and metabolism. A classical effect of thyroxine, instrumental in delineating the mode of action of the hormone, is the triggering of amphibian metamorphosis (2). This change from larva to the adult animal is accompanied biochemically by a change in the mode of amino acid nitrogen excretion. Larvae excrete nitrogen in the form of NH+4, whereas frogs excrete it as urea. Thyroxine induces the biosynthesis of key enzymes involved in the production of urea by molecular mechanisms similar to those of steroid hormones. These hormones bind to intracellular receptors, belonging to the superfamily of nuclear receptors (3). Two T3 receptor genes have been found, a and b, located on human chromosomes 17 and 3, respectively. The respective receptors (TRa and TRb) have been identified. TRa is the c-erbA protooncogene. Two different isoforms of b (TRb1 and TRb2) have been isolated and exhibit tissue-specific expression. The receptors recognize the respective hormone response elements of DNA, to which they bind either as homodimers or as heterodimers with other nuclear proteins, such as RXR (retinoid X-receptor). In some cases, the receptor binds in the absence of hormone and acts as a repressor. Derepression is accomplished by its ligand binding to the receptor (4). In other cases, the hormone-receptor complex acts as a positive regulator of transcription.
Thyroid hormone deficiency during embryogenesis results in mental and somatic developmental defects (cretinism). Experimental extirpation of the thyroid gland leads to delayed growth and sexual maturation. In the fully developed organism, thyroid hormones show general metabolic effects, increasing metabolic rates, O2 consumption, and thermogenesis. These effects result from the induction of the Na+/K+ ATPase. The synthesis of RNA and proteins are also stimulated. Furthermore, the biosynthesis of other enzymes (eg, the mitochondrial glycerol-1-phosphate dehydrogenase) are also induced by the thyroid hormones. Thyroid hormones stimulate both lipogenesis and lipolysis. Lipogenesis is the result of induction of biosynthesis of enzymes of the lipogenic pathway (malate dehydrogenase, glucose 6-phosphate dehydrogenase, and fatty acid synthetase). In hypothyroidism, lipoprotein metabolism is altered, serum concentrations of LDL-cholesterol are increased, and hepatic lipase activity is decreased. Thyroid hormones reduce systemic vascular resistance, enhance cardiac contractility, and have a chronotropic effect. T3 stimulates transcription of myosin heavy-chain_a and inhibits expression of heavy-chain b-genes.
