Metabolism Of Thyroid Hormones

Because T4 is bound much more tightly by plasma proteins then T3, a greater fraction of T3 is free to diffuse out of the vascular compartment and into cells where it can produce its biological effects or be degraded. Consequently, it is not surprising that the half-time for disappearance of an administered dose of 125I-labeled T3 is only one-sixth of that for T4, or that the lag time needed to observe effects of T3 is considerably shorter than that needed for T4. However, because of the binding proteins, both T4 and T3 have unusually long half-lives in plasma, measured in days rather than seconds or minutes (Fig. 7). It is noteworthy that the half-lives of T3 and T4 are increased with thyroid deficiency and shortened with hyperthyroidism.

days after I.V. injection of radioactive T3 or T4

FIGURE 7 Rate of loss of serum radioactivity after injection of labeled thyroxine or triiodothyronine into human subjects. (Plotted from data of Nicoloff JD, Low JC, Dussault JH, et al. Simultaneous measurement of thyroxine and triiodothyronine peripheral turnover kinetics in man. J Clin Invest 1972;51:473.)

days after I.V. injection of radioactive T3 or T4

FIGURE 7 Rate of loss of serum radioactivity after injection of labeled thyroxine or triiodothyronine into human subjects. (Plotted from data of Nicoloff JD, Low JC, Dussault JH, et al. Simultaneous measurement of thyroxine and triiodothyronine peripheral turnover kinetics in man. J Clin Invest 1972;51:473.)

Although the main secretory product of the thyroid gland and the major form of thyroid hormone present in the circulating plasma reservoir is T4, abundant evidence indicates that it is T3 and not T4 that binds to the thyroid hormone receptor (see later discussion). In fact, T4 can be considered to be a prohormone that serves as the precursor for extrathyroidal formation of T3.

Observations in human subjects confirm that T3 is actually formed extrathyroidally and can account for most of the biological activity of the thyroid gland. Thyroidectomized subjects given pure T4 in physiologic amounts have normal amounts of T3 in their circulation. Furthermore, the rate of metabolism of T3 in normal subjects is such that about 30 mg of T3 is replaced daily, even though the thyroid gland secretes only 5 mg each day. Thus, nearly 85% of the T3 that turns over each day must be formed by deiodination of T4 in extrathyroidal tissues. This extrathyroidal formation of T3 consumes about 35% of the T4 secreted each day. The remainder is degraded to inactive metabolites.

Extrathyroidal metabolism of T4 centers around selective and sequential removal of iodine from the thyronine nucleus catalyzed by three different enzymes called deiodinases (Fig. 8). The type I deiodinase is expressed mainly in the liver and kidney, but is also found in the central nervous system, the anterior pituitary gland, and the thyroid gland itself. The type I deiodinase is a membrane-bound enzyme with its catalytic domain oriented to face the cytoplasm. Despite its intracellular location, however, T3 formed by deio-dination, especially in the liver and kidney, readily escapes into the circulation and accounts for about 80% of the T3 in blood. The type I deiodinase can remove an iodine molecule either from the outer (phenolic) ring of thyroxine; 3, 5, 3', 5'-tetraiodothyronine; T4

thyroxine; 3, 5, 3', 5'-tetraiodothyronine; T4

FIGURE 8 Metabolism of thyroxine. About 90% of thyroxine is metabolized by sequential deiodination catalyzed by deiodinases (types I, II and III); the first step removes an iodine from either the phenolic or tyrosyl ring producing an active (T3) or an inactive (rT3) compound. Subsequent deiodinations continue until all of the iodine is recovered from the thyronine nucleus. Dark blue arrows designate deiodination of the phenolic ring and light blue arrows indicate deiodination of the tyrosyl ring. Less than 10% of thyroxine is metabolized by shortening the alanine side chain prior to deiodination.

T4, or from the inner (tyrosyl) ring. Iodines in the phenolic ring are designated 3' and 5', whereas iodines in the inner ring are designated simply 3 and 5. The 3 and 5 positions on either ring are chemically equivalent, but there are profound functional consequences of removing an iodine from the inner or outer rings of thyroxine. Removing an iodine from the outer ring produces 3',3,5 triiodothyronine, usually designated as T3, and converts thyroxine to the form that binds to the thyroid hormone receptor. Removal of an iodine from the inner ring produces 3',5',3 triiodothyronine, also called reverse T3 (rT3), which cannot bind to the thyroid hormone receptor and can only be further deiodinated.

The type II deiodinase is absent from the liver, but is found in many extrahepatic tissues including the brain and pituitary gland where it is thought to produce T3 to meet local tissue demands independently of circulating T3, although these tissues can also take up T3 from the blood. Expression of the type II deiodinase is regulated by other hormones; its expression is highest when blood concentrations of T4 are low. In addition, hormones that act through the cyclic AMP second messenger system (Chapter 2) and growth factors stimulate type II deiodinase expression. These characteristics support the idea that this enzyme may provide T3 to meet local demands.

The type III deiodinase removes an iodine from the tyrosyl ring of T4 or T3, and hence its function is solely degradative. It is widely expressed by many tissues throughout the body. Reverse T3, a product of both the type I and type III deiodinases, may be further deiodinated by the type III deiodinase by removal of the second iodide from inner ring (Fig. 8). Reverse T3 is also a favored substrate for the type I deiodinase, and although it is formed at a similar rate as T3 it is degraded much faster than T3. Some rT3 escapes into the bloodstream where it is avidly bound to TBG and TTR.

All three deiodinases can catalyze the oxidative removal of iodine from partially deiodinated hormone metabolites, and through their joint actions the thyr-onine nucleus can be completely stripped of iodine. The liberated iodide is then available to be taken up by the thyroid and recycled into hormone. A quantitatively less important route for degradation of thyroid hormones includes shortening of the alanine side chain to produce tetraiodothyroacetic acid (Tetrac) and its subsequent deiodination products. Thyroid hormones are also conjugated with glucuronic acid and excreted intact in the bile. Bacteria in the intestine can split the glucur-onide bond, and some of the thyroxine liberated can be taken up from the intestine and be returned to the general circulation. This cycle of excretion in bile and absorption from the intestine is called the enterohepatic circulation and may be of importance in maintaining normal thyroid economy when thyroid function is marginal or dietary iodide is scarce. Thyroxine is one of the few naturally occurring hormones that is sufficiently resistant to intestinal and hepatic destruction that it can readily be given by mouth.

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