Abstract
Over the last decades, thyroid hormone metabolites (THMs) received marked attention as it has been demonstrated that they are bioactive compounds. Their concentrations were determined by immunoassay or mass-spectrometry methods. Among those metabolites, 3,5-diiodothyronine (3,5-T2), occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations similar to those of T4 and T3, at least based on data from rodent models. However, the immunoassay-based measurements in human sera revealed remarkable variations depending on antibodies used in the assays and thus need to be interpreted with caution. In clinical experimental approaches in euthyroid volunteers and hypothyroid patients using the immunoassay as the analytical tool no evidence of formation of 3,5-T2 from its putative precursors T4 or T3 was found, nor was any support found for the assumption that 3,5-T2 might represent a direct precursor for serum 3-T1-AM generated by combined deiodination and decarboxylation from 3,5-T2, as previously documented for mouse intestinal mucosa. We hypothesized that lowered endogenous production of 3,5-T2 in patients requiring T4 replacement therapy after thyroidectomy or for treatment of autoimmune thyroid disease, compared to production of 3,5-T2 in individuals with intact thyroid glands might contribute to the discontent seen in a subset of patients with this therapeutic regimen. So far, our observations do not support this assumption. However, the unexpected association between high serum 3,5-T2 and elevated urinary concentrations of metabolites related to coffee consumption requires further studies for an explanation. Elevated 3,5-T2 serum concentrations were found in several situations including impaired renal function, chronic dialysis, sepsis, non-survival in the ICU as well as post-operative atrial fibrillation (POAF) in studies using a monoclonal antibody-based chemoluminescence immunoassay. Pilot analysis of human sera using LC-linear-ion-trap-mass-spectrometry yielded 3,5-T2 concentrations below the limit of quantification in the majority of cases, thus the divergent results of both methods need to be reconciliated by further studies. Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle anabolic, slimming or fitness drug, easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing adverse cardiac side effects. 3,5-T2 escapes regular detection by commercially available clinical routine assays used for thyroid function tests, which may be seriously disrupted in individuals self-administering 3,5-T2 obtained over-the counter or from other sources.
Highlights
Endogenous Thyroid Hormones and Their MetabolitesA 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]
The initial hypothesis that rT3 might act as potent inhibitor of DIO1 or DIO2 during T3 formation [12, 13] could not be supported by in vivo experiments due to its short half-life and insufficient local concentrations [14]
Following the detection of the thyromimetically active T3 in human serum and its production from T4 in athyreotic humans supplemented with L-thyroxine [21, 22], attempts were made to quantify concentration of 3,5-T2 in human
Summary
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]. 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 T3) actions at the integrin receptor signaling. Whether this has physiological relevance beyond these pharmacological approaches, mainly tested so far in cancer or stem cells, remains to be demonstrated. Indirect evidence mainly from in vivo experiments in rodents suggests that 3,5-T2, a physiologically active endogenous thyroid hormone metabolite, is formed by a further 3′-deiodination reaction catalyze by these (one of these) two deiodinase enzymes. Following the detection of the thyromimetically active T3 in human serum and its production from T4 in athyreotic humans supplemented with L-thyroxine [21, 22], attempts were made to quantify concentration of 3,5-T2 in human
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