Alternate Pathways of Thyroid Hormone Metabolism

Abstract

The major thyroid hormone (TH) secreted by the thyroid gland is thyroxine (T(4)). Triiodothyronine (T(3)), formed chiefly by deiodination of T(4), is the active hormone at the nuclear receptor, and it is generally accepted that deiodination is the major pathway regulating T(3) bioavailability in mammalian tissues. The alternate pathways, sulfation and glucuronidation of the phenolic hydroxyl group of iodothyronines, the oxidative deamination and decarboxylation of the alanine side chain to form iodothyroacetic acids, and ether link cleavage provide additional mechanisms for regulating the supply of active hormone. Sulfation may play a general role in regulation of iodothyronine metabolism, since sulfation of T(4) and T(3) markedly accelerates deiodination to the inactive metabolites, reverse triiodothyronine (rT(3)) and T(2). Sulfoconjugation is prominent during intrauterine development, particularly in the precocial species in the last trimester including humans and sheep, where it may serve both to regulate the supply of T(3), via sulfation followed by deiodination, and to facilitate maternal-fetal exchange of sulfated iodothyronines (e.g., 3,3'-diiodothyronine sulfate [T(2)S]). The resulting low serum T(3) may be important for normal fetal development in the late gestation. The possibility that T(2)S or its derivative, transferred from the fetus and appearing in maternal serum or urine, can serve as a marker of fetal thyroid function is being studied. Glucuronidation of TH often precedes biliary-fecal excretion of hormone. In rats, stimulation of glucuronidation by various drugs and toxins may lead to lower T(4) and T(3) levels, provocation of thyrotropin (TSH) secretion, and goiter. In man, drug induced stimulation of glucuronidation is limited to T(4), and does not usually compromise normal thyroid function. However, in hypothyroid subjects, higher doses of TH may be required to maintain euthyroidism when these drugs are given. In addition, glucuronidates and sulfated iodothyronines can be hydrolyzed to their precursors in gastrointestinal tract and various tissues. Thus, these conjugates can serve as a reservoir for biologically active iodothyronines (e.g., T(4), T(3), or T(2)). The acetic acid derivatives of T(4), tetrac and triac, are minor products in normal thyroid physiology. However, triac has a different pattern of receptor affinity than T(3), binding preferentially to the beta receptor. This makes it useful in the treatment of the syndrome of resistance to thyroid hormone action, where the typical mutation affects only the beta receptor. Thus, adequate binding to certain mutated beta receptors can be achieved without excessive stimulation of alpha receptors, which predominate in the heart. Ether link cleavage of TH is also a minor pathway in normal subjects. However, this pathway may become important during infections, when augmented TH breakdown by ether-link cleavage (ELC) may assist in bactericidal activity. There is a recent claim that decarboxylated derivates of thyronines, that is, monoiodothy...

The history of a developmental stage: Metamorphosis in chordates

“…4) and were shown to be active: for instance TRIAC, the T 3 deaminated derivative displays strong themogenic effects and has a higher affinity for TR than T 3 . This compound is less stable than T 3 , but its production represents 14% of T 3 metabolism (Moreno et al, 2008;Wu et al, 2005). Nonetheless, the general biological action of those TH derivatives remains vague (Wu et al, 2005).…”

“…This compound is less stable than T 3 , but its production represents 14% of T 3 metabolism (Moreno et al, 2008;Wu et al, 2005). Nonetheless, the general biological action of those TH derivatives remains vague (Wu et al, 2005). In other chordates, no exhaustive repertoire is available.…”

“…(8) There are also alternative TH pathways, like sulfatation and glucuronidation, mostly resulting in production of inactive T 3 derivatives, targeted for degradation. (9) However, some alternative active forms are also produced, like the deaminated form of T 3 , TRIAC, which is a very potent, but very unstable TH derivative (see Wu et al, 2005) (Figs. 4 and 5).…”

“…It is important to keep in mind that TH metabolism is not limited to T 3 and T 4 in mammals or amphibians: other TH derivatives are produced, like deiodinated, decarboxylated or deaminated derivatives, as well as sulfated and glucuronidated conjugates (Wu et al, 2005) (Figs. 4 and 5).…”

Thyroid hormones in small ruminants: effects of endogenous, environmental and nutritional factors

“…Oxidative deamination and decarboxylation occurring in the kidney, liver and muscle, form acid metabolites, which maintain a certain biological activity, but do not contribute to the hormone action in euthyroid subjects because they are produced in very small amounts (Greenspan, 2001). Decarboxylated derivatives of iodothyronines, such as monoiodothyronamine and thyronamine, actually represent a very interesting field of investigation, because they may have some biological actions, even different from those of TH (Wu et al, 2005).…”