Thyroid Hormones and Derivatives: Endogenous Thyroid Hormones and Their Targets

Abstract

More than a century after the discovery of L-Thyroxine, the main thyroid hormone secreted solely by the thyroid gland, several metabolites of this iodinated, tyrosine-derived ancestral hormone have been identified. These are utilized as hormones during development, differentiation, metamorphosis, and regulation of most biochemical reactions in vertebrates and their precursor species. Among those metabolites are the thyromimetically active 3,3',5-Triiodo-L-thyronine (T3) and 3,5-Diiodo-L-thronine, reverse-T3 (3,3',5'-Triiodo-L-thyronine) with still unclear function, the recently re-discovered thyronamines (e.g., 3-Iodo-thyronamine), which exert in part T3-antagonistic functions, the thyroacetic acids (e.g., Tetrac and Triac), as well as various sulfated or glucuronidated metabolites of this panel of iodinated signaling compounds. In the blood most of these hydrophobic metabolites are tightly bound to the serum distributor proteins thyroxine binding globulin (TBG), transthyretin (TTR), albumin or apolipoprotein B100. Cellular import and export of these charged, highly hydrophobic amino acid derivatives requires a number of cell-membrane transporters or facilitators such as MCT8 or MCT10 and members of the OATP and LAT families of transporters. Depending on their structure, the thyroid hormone metabolites exert their cellular action by binding and thus modulating the function of various receptors systems (e.g., ανβ3 integrin receptor and transient receptor potential channels (TRPM8) of the cell membrane), in part linked to intracellular downstream kinase signaling cascades, and several isoforms of membrane-associated, mitochondrial or nuclear thyroid hormone receptors (TR), which are members of the c-erbA family of ligand-modulated transcription factors. Intracellular deiodinase selenoenzymes, which obligatory are membrane integrated enzymes, ornithine decarboxylase and monoamine oxidases control local availability of biologically active thyroid hormone metabolites. Inactivation of thyroid hormone metabolites occurs mainly by deiodination, sulfation or glucuronidation, reactions which favor their renal or fecal elimination.

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

“…The TH metabolite 3,5-T2, possibly formed from its precursor T3 (Figure 1), has recently attracted great interest for several reasons (3,9,15). 3,5-T2 has been considered the main biological active metabolite of T3, formed via further phenolic ring deiodination from T3 (Figure 1).…”

“…A century of thyroxine research has led to the commonly held opinion in the thyroid hormone community that 3,3 ′ ,5,5 ′tetraiodo-L-thyronine (L-Thyroxine, L-T4), which is solely produced by the thyroid gland, serves as a prohormone while T3 (3,3 ′ 5-triiodo-L-thyronine), in part secreted by the thyroid gland, is mainly generated in various extra-thyroidal tissues by either type 1 or type 2 deiodinase (DIO1, DIO2) selenoenzymes (1)(2)(3). T3 exerts the majority of known thyroid hormone (TH) effects at the tissue and cellular level, including hypothalamic and pituitary negative feedback regulation of the hypothalamuspituitary-thyroid-periphery (HPTP) axis (4)(5)(6).…”

“…Over the last years, some evidence has been presented that T4 also binds to cell membrane-located ανβ3 integrin receptors which exert rapid signaling via various kinase and intracellular pathways, especially in tumor cells and stem cells (7,8). The T4 metabolite Tetrac, a deaminated side chain metabolite, present in human serum at concentrations similar to those of T3 (3,9) antagonizes such T4 (and also T3) actions at the integrin receptor signaling. However, whether this has physiological relevance beyond these pharmacological approaches, mainly tested so far in cancer or stem cells, remains to be demonstrated.…”

“…However, whether this has physiological relevance beyond these pharmacological approaches, mainly tested so far in cancer or stem cells, remains to be demonstrated. A further metabolite of T4 found in human serum, 3,3 ′ ,5 ′ -triiodothyronine (reverse T3, rT3) has been studied over the last four decades because its production by the type 3 deiodinase (DIO3), also a selenoprotein, is increased under conditions when T3 production by DIO1 is impaired (3,9) as well as during development in many tissues, when DIO2 activity is decreased (10). As rT3 is also degraded by DIO1, such conditions of high rT3 and low T3 (and T4) serum concentrations, summarized under the term "nonthyroidal critical illness" or "low T3 syndrome, " have caught the attention of clinicians attempting to use this constellation as a diagnostic or predictive readout.…”

Pesticides With Potential Thyroid Hormone-Disrupting Effects: A Review of Recent Data

“…In humans, TH is essential for the development of the brain, inner ear, eye, heart, kidneys, bone and skeletal muscle, amongst other tissues (22), but also for fine regulation of energy metabolism (23). The essential role of TH during vertebrate development has been amply reviewed (24)(25)(26), however neurodevelopment warrants special attention. Strikingly, THs are crucial for normal brain development which is dramatically illustrated by cretinism, a syndrome induced by a severe lack of TH or iodine during embryo-fetal and post-natal development (27).…”