Indirect evidence mainly from experiments in rodents suggests that 3,5-T2, a physiologically active endogenous thyroid hormone metabolite, is formed by a further 3-deiodination reaction also catalyze by these (one of these) two deiodinase enzymes. Therefore, we intended to test several hypotheses using clinical experimental data, animal experiments, and cell culture approaches as well as recently developed novel analytical tools such as the sensitive chemoluminescence immunoassay (CLIA), highly specific for 3,5-T2 detection in human serum (20). exhibited that they are bioactive compounds. Their concentrations were determined by immunoassay or mass-spectrometry alpha-Amyloid Precursor Protein Modulator methods. Among those metabolites, 3,5-diiodothyronine (3,5-T2), occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations much like those of T4 and T3, at least based on data from rodent models. However, the immunoassay-based measurements in human sera revealed amazing variations depending on antibodies used in the assays and thus need to be interpreted with caution. In clinical experimental methods 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 Rabbit Polyclonal to STAT1 further studies. Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle mass anabolic, slimming or fitness drug, very easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing alpha-Amyloid Precursor Protein Modulator adverse cardiac side effects. 3,5-T2 escapes regular detection by commercially available clinical routine assays utilized for thyroid function assessments, which may be seriously disrupted in individuals self-administering 3,5-T2 obtained over-the counter or from other sources. experiments due to its short half-life and insufficient local concentrations (14). These observations did not support the hypothesis of rT3 acting as an autonomous regulator of extrathyroidal T3 formation under (patho-)physiological conditions. 3,5-T2 Is usually a Further Endogenous TH Metabolite With Thyromimetic Potency The TH metabolite 3,5-T2, possibly created from its precursor T3 (Physique 1), has recently drawn great interest for several reasons (3, 9, 15). 3,5-T2 has been considered the main biological active metabolite of T3, created via further phenolic ring deiodination from T3 (Physique 1). The TH metabolite 3,5-T2 is found in blood and at even higher concentrations in several tissues. Various groups have exhibited that 3,5-T2, in addition to its thyromimetic action at the classical T3 receptors at high concentrations, exerts quick direct effects on mitochondria (6, 16C19), which might be beneficial in terms of stimulation of oxygen consumption, increased hepatic, and muscular lipid metabolismall of these effects appear as potentially favorable in global alpha-Amyloid Precursor Protein Modulator attempts to combat steatosis in liver and other tissues. Open in a separate window Physique 1 Postulated pathway of biosynthesis of 3,5-T2 from its putative precursors T4 and T3. The physique shows the structural formulas of L-T4, the prohormone, synthetized, and secreted by the thyroid gland, and its 5-deiodination product L-T3, which is usually secreted in part by the thyroid gland (ca. 80%) or generated in extrathyroidal tissues by the two selenoenzyme 5-deiodinase type 1 or type 2, which both remove the 5-iodine atom of L-T4 in a reductive two-substrate reaction with a so far unknown physiological cofactor. Indirect evidence mainly from experiments in rodents suggests that 3,5-T2, a physiologically active endogenous thyroid hormone metabolite, is usually formed by a further 3-deiodination reaction also catalyze by these (one of these) two deiodinase enzymes. Therefore, we intended to test several hypotheses using clinical experimental data, animal experiments,.