Thyroid hormone 3,5,3′-triiodothyronine (T3) and its precursor thyroxine (T4) are iodinated compounds known to influence gene expression in virtually every vertebrate tissue. Fundamentally, thyroid hormone signaling results from the interaction of nuclear thyroid hormone receptors (TRs) with specific target gene promoters, a process that can either enhance or repress transcription. This process is modulated via binding of thyroid hormone, the ligand, to the TRs, which results in alterations in the composition of the transcriptional complex (1
). Signaling through this pathway is, of course, sensitive to changes in serum thyroid hormone concentrations, and the consequences of deranged thyroid function, as seen in patients with Graves hyperthyroidism or Hashimoto thyroiditis, have been recognized for over 100 years. The modern paradigm of thyroid hormone action also recognizes that thyroid hormone signaling in individual tissues can change even as serum hormone concentrations remain normal, thanks to local activation or inactivation of thyroid hormone (4
). The underlying mechanism of these phenomena is deiodination.
The iodothyronine deiodinases types I, II, and III (D1, D2, and D3, respectively) regulate the activity of thyroid hormone via removal of specific iodine moieties from the precursor molecule T4 (Figures and ). These 3 enzymes constitute a group of dimeric integral membrane thioredoxin fold–containing proteins (7
) that can activate or inactivate thyroid hormone, depending on whether they act on the phenolic or tyrosil rings of the iodothyronines, respectively (11
). D2 generates the active form of thyroid hormone T3 via deiodination of T4. In contrast, D3 inactivates T3 and, to a lesser extent, prevents T4 from being activated. Finally, D1 is a kinetically inefficient enzyme that activates or inactivates T4 on an equimolar basis, and its role in health remains to be clarified. In general, a given cell type will express only 1 type of deiodinase at a given time, though some tissues express none, and all 3 types of activity have been measured in the pituitary gland (Table ).
Human iodothyronine selenodeiodinases
The activity of the deiodinases can substantially alter thyroid hormone signaling in a given cell (5
). While the total concentration of T4 exceeds that of T3 by 2 orders of magnitude, T4 is tightly bound to carrier proteins, and the free concentrations of T4 and T3 are quite similar. Both enter the cell via transporters, including the monocarboxylate transporter 8 and the organic anion transporting polypeptide C1 (12
). Once inside the cell, T4 can be activated via conversion to T3 by the D2 pathway, such that the cytoplasmic pool of T3 includes both T3 from the plasma and T3 generated by D2 (Figure ). Alternatively, D3 acts at the plasma membrane to decrease local T3 concentrations (Figure ). Thus, the deiodinases are critical determinants of the cytoplasmic T3 pool and therefore modulate nuclear T3 concentration and TR saturation (13
). In normal rats, the D2 pathway is responsible for about half of the nuclear T3 content in the brain, pituitary gland, and brown adipose tissue (14
Pathways regulating D2 expression and thyroid hormone signaling.
Abnormalities in deiodinase activity are important in a number of clinical settings. The best-known example is critical illness, during which changes in deiodinase activities are linked to complex alterations in thyroid hormone metabolism (16
). Another common setting is patients being treated with amiodarone, an antiarrhythmic drug well known to alter thyroid function tests via both direct actions on the thyroid and inhibition of T4 activation (17
). While rare, vascular tumors with high D3 activity have been shown to cause severe hypothyroidism in both adults and children (18
). Increased D3 activity as a general mechanism may have much broader clinical relevance; as fetoplacental and uterine D3 activity increase dramatically during pregnancy (20
), this activity may be the cause of increased l-thyroxine requirements in pregnant patients with hypothyroidism (22
). Individuals with genetic alterations in the deiodinases have not yet been identified, though the clinical implications of several polymorphisms are under investigation (23
). Understanding the signaling pathways these enzymes are involved with could have therapeutic utility for all of these clinical settings. However, the real excitement in this field stems from the discoveries that deiodinases can participate in both the bile acid and Hedgehog signaling cascades (Figure ) (28
). As a result of this linkage, novel roles for these enzymes in the realms of metabolic control and developmental biology have become apparent.