Endocrine Abstracts

The prohormone thyroxine (T4) is the major product secreted by the thyroid gland, while most actions of thyroid hormone (TH) are initiated by binding of the active hormone 3,3′,5-triiodothyronine (T3) to nuclear receptors. The biological activity of TH is thus determined by the intracellular T3 concentration in target tissues, which depends on 1) the circulating concentrations of T4 and T3, 2) the activity of deiodinases catalyzing the conversion of T4 to T3 or to receptor-inactive metabolites, and 3) the activity of transporters which facilitate the cellular uptake and/or efflux of T4 and T3. As in many animals, administration of T4 or T3 induces the metamorphosis of the invertebrate amphioxus. However, T3 is incapable of stimulating the TH receptor in amphioxus in vitro, in contrast to the potent stimulation by 3,3′,5-triiodothyro-acetic acid (Triac)1. Furthermore, a deiodinase has been characterized in amphioxus, which is inactive towards iodothyronines but effectively deiodinates Triac2. Together, these findings suggest that Triac is the active TH in amphioxus. Early studies of the metabolism of T3 in humans and animals have indicated the formation of Triac but the exact nature of this process has not been established3. The first step in the conversion of T3 to Triac is likely catalyzed by one or more aminotransferases, resulting in the formation of 3,3′,5-triiodothyropyruvic acid. The latter may then be oxidized to Triac, but it is unclear what enzyme, if any, is involved in this oxidation. Recent studies in our lab have resulted in better insights in the pathway by which T3 is converted to Triac. Triac has been used for TSH-suppressive therapy in patients with thyroid cancer or patients with thyroid hormone resistance, based on a greater central than peripheral activity of Triac. It is now also tested as a therapy for patients with severe X-linked psychomotor retardation (Allan-Herndon-Dudley syndrome, AHDS) caused by mutations in the TH transporter MCT8. MCT8 is essential for TH transport into and inside the brain, and TH deficiency in the developing brain results in severe neurological deficits. Supported by in vitro and animal experiments, Triac does not require functional MCT8 for transport into brain cells, and would thus be effective in restoring thyromimetic activity in the brain of AHDS patients3.

References

Paris M et al. Curr Biol. 2008; 18: 825-30.

Klootwijk W et al. Endocrinology 2011; 152: 3259-67.

Groeneweg S et al. J Endocrinol. 2017; 234: R99-R121.