Triiodothyronine conversion

Triiodothyronine conversion binding in rat cerebral cortex and cerebellum, J. Clin. Investigation 64 935 (1980). 

The formation of triiodothyronine (T3) and tetra-iodothyronine (thyroxine T4) (see Figure 42—2) illustrates many of the principles of diversity discussed in this chapter. These hormones require a rare element (iodine) for bioactivity they are synthesized as part of a very large precursor molecule (thyroglobuhn) they are stored in an intracellular reservoir (colloid) and there is peripheral conversion of T4 to T3, which is a much more active hormone. 

The concentration of Li+ in the thyroid is three to four times that in serum [179]. It is thought that Li+ may be concentrated in the thyroid gland by a mechanism similar to the incorporation of iodide, I-, resulting in competition between Li+ and I the levels of intracellular 1 decrease when those of Li+ increase, and vice versa [182]. Li+ inhibits both the ability of the gland to accumulate 1 and the release of iodine from the gland. In vitro, Li+ has no effect on thyroid peroxidase, the enzyme that catalyzes the incorporation of I" into tyrosyl residues leading to thyroidal hormone synthesis, but does increase the activity of iodotyrosine-deio-dinase, which catalyzes the reductive deiodination of iodotyrosyls, thus maintaining the levels of intracellular I [182]. The increase in iodoty-rosine-deiodinase activity is probably a response to the Li+-induced decrease in the concentration of thyroidal I". Li+ has no effect on the conversion of thyroxine to triiodothyronine. The overall effect of this competition between Li+ and 1 is, therefore, reduced levels of thyroid hormone in the presence of Li+. 

The Class III effects of amiodarone develop over several weeks. This time-course is similar to that seen in thyroid gland ablation [25]. It is well known that patients with hypothyroidism have long QT intervals which are indicative of prolonged action potentials. Amiodarone has been shown to inhibit the conversion of thyroxine (T4) to triiodothyronine (T3) both in human subjects [26] and in vitro [27]. It has been argued that the Class III effects of amiodarone are due to its effects on thyroid hormones [28]. Others, however, argue that there is no relationship between prolongation of ventricular refractory period by amiodarone and thyroid state [29]. 

T3 levels in the blood are low with a decreased rate of formation from thyroxine bnt increased conversion of the latter to reverse triiodothyronine (rTs). 

The thyroid releases predominantly thyroxine (T4). However, the active form appears to be triiodothyronine (T3) T4 is converted in part to T3, receptor affinity in target organs being 10-fold higher for T3. The effect of T3 develops more rapidly and has a shorter duration than does that of T4. Plasma elimination tip for T4 is about 7 d that for T3, however, is only 1.5 d. Conversion of T4 to T3 releases iodide 150 pg T4 contains 100 pg of iodine. 

Thyroid abnormalities Am o6arone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3), prompting increased T4levels, increased levels of inactive reverse T3 and decreased levels of T3. It is also a potential source of large amounts... 

Hyperthyroidism is characterized by an enhanced sympathetic activity, especially in the heart. The salutary inhibition of jS-adrenoceptors under these conditions can be achieved by all jS-blocker alike. Some of the clinically used compounds are able to reduce the conversion (de-iodination) of thyroxine (T4) to the active 3,5,3 -Triiodothyronine (T3)... 

Amiodarone inhibits the peripheral and possibly in-trapituitary conversion of thyroxine (T4) to triiodothyronine (Tj) by inhibiting 5 -deiodination. The serum concentration of T4 is increased by a decrease in its clearance, and thyroid synthesis is increased by a reduced suppression of the pituitary thyrotropin T3. The concentration of T3 in the serum decreases, and reverse T3 appears in increased amounts. Despite these changes, most patients appear to be maintained in an euthyroid state. Manifestations of both hypothyroidism and hyperthyroidism have been reported. 

Hyperthyroidism Propranolol blocks the peripheral conversion of thyroxine to triiodothyronine. It controls palpitation, nervousness, tremor sweating etc. 

Excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism, especially in relation to the heart (see Chapter 38). The 13 antagonists are beneficial in this condition. The effects presumably relate to blockade of adrenoceptors and perhaps in part to the inhibition of peripheral conversion of thyroxine to triiodothyronine. The latter action may vary from one 13 antagonist to another. Propranolol has been used extensively in patients with thyroid storm (severe hyperthyroidism) it is used cautiously in patients with this condition to control supraventricular tachycardias that often precipitate heart failure. 

Antithyroid drugs may also suppress lymphocytic infiltration into the thyroid and thereby directly modulate the basic disorder of autoimmune hyperthyroidism (SEDA-6, 364 SEDA-9, 344). Propylthiouracil, but not the thioimidazoles, also inhibits the conversion of thyroxine to its more active derivative triiodothyronine. This effect is significant during high-dose treatment, and propylthiouracil may therefore be preferred if a more rapid onset of action is desired, for example thyrotoxic crisis, although clear experimental proof of the advantageous effect is still lacking (3). 

Despite the fact that she was clinically euthyroid, the authors suggested that this patient had amiodarone-induced hyperthyroidism. However, amiodarone inhibits the peripheral conversion of thyroxine to triiodothyronine it can therefore increase the serum thyroxine and suppress the serum TSH, as in this case. On the other hand, the reduced uptake by the thyroid gland is consistent with type 2 amiodarone-induced hyperthyroidism. The authors did not report the serum concentrations of free thyroxine and triiodothyronine. 

Heyma P, Larkins RG, Higginbotham L, Ng KW. D-pro-pranolol and DL-propranolol both decrease conversion of L-thyroxine to L-triiodothyronine. BMJ 1980 281(6232) ... 

An advantage of T-3/L-triiodothyronine administration over T-4/L-thyroxine was the lack of dependence upon the liver enzyme responsible for T-4/T-3 conversion. During diet restricted periods the liver naturally decreases the liver enzyme levels as a control measure to prevent metabolic rate induced starvation. Just as the liver increases production of this enzyme in response to elevated calorie intake it also reduces levels in response to decreased calorie intake. Remember that T-4 /L-thyroxine is only 20% as active as T-3/L-triiodothyronine. 

Synthroid is a man-made synthetically manufactured version of T-4/L-thyroxine. The average person produces about 76 MCG/d of T-4/L-thyroxine which is then converted by the liver into the more active T-3/L-triiodothyronine. This is true of the oral T-4/L-thyroxine medications as well. The average conversion rate of T-4 to T-3 is about 30-33%/ MCG. Since the conversion of T-4 to T-3 is dependent upon adequate levels of since and selenium, athletes commonly increase daily intake of these minerals during synthetic T-4/L-thyroxine use. 

Because thyroxine contains four iodine residues, this compound is also referred to by the abbreviation T4. Likewise, triiodothyronine contains three iodine residues, hence the abbreviation T3. There has been considerable discussion about which hormone exerts the primary physiologic effects. Plasma levels of T4 are much higher than T3 levels, but T3 may exert most of the physiologic effects on various tissues, which suggests that T4 is a precursor to T3 and that the conversion of T4 to T3 occurs in peripheral tissues.23 Regardless of which hormone ultimately affects cellular metabolism, both T4 and T3 are needed for normal thyroid function. 

Selenium is an essential trace element, being important in at least two critical enzymes, the antioxidant glutathione peroxidase (GPx), and type 1 iodothyronine deiodinase. GPx converts hydrogen peroxide to water, in the presence of reduced glutathione, while iodothyronine deiodinase catalyzes the conversion of thyroxine to triiodothyronine, the physiologically active hormone species. 

Phenytoin decreases the urinary excretion of 17-ketosteroids and 17-hydroxycorticosteroids by stimulating the conversion of cortisol to 6-P-hydroxycortisol it also diminishes serum FSH and the sperm count in semen, and thereby reduces fertility, Phenytoin also lowers the serum thyroxine concentration, probably by competitive displacement of thyroxine from its protein-binding sites free thyroxine also tends to be low. Serum triiodothyronine is low, probably as a result of stimulated metabohsm in the liver, but the concentration of TSH is unaffected by the altered thyroxine metabolism. 

Triiodothyronine (Ta) Tyr Peripheral conversion from thyroxine (T ) thyroid Many effects, e.g., regulation of metabolism. 

Thyroid Triiodothyronine (T3) Thyroxine (T4) (after conversion to T3) General stimulation of many cellular reactions... 

Other drugs that are useful in the rapid treatment of the severely thyrotoxic patient are agents that inhibit the peripheral conversion of thyroxine to triiodothyronine. Dexamethasone (0.5 to 1 mg two to four times daily), and the iodinated radiological contrast agents iopanoic acid (Telepaque, 500 to 1000 mg once daily), and sodium ipodate (Qragrafin, 500 to 1000 mg once daily) are effective in preoperative preparation. Neither iopanoic acid nor sodium ipodate is available in the United States. Cholestyramine has been used in severely toxic patients to bind thyroid hormones in the gut and thus block the enterohepatic circulation of the iodothyronines. 

Lithium enhances the uptake of tryptophan and increases the synthesis of serotonin. It is also thought to decrease the reuptake of monamine neurotransmitters (e.g., catecholamines and serotonin). Reactions can be idiosyncratic, however, as lithium also decreases the conversion of thyroxine to triiodothyronine in the CNS. 

---