Evidence for Extrathyroidal Formation of 3-Iodothyronamine in Humans as Provided by a Novel Monoclonal Antibody-Based Chemiluminescent Serum Immunoassay

Hoefig, Carolin S.; Köhrle, Josef; Brabant, Georg; Dixit, Kashinath; Yap, Beng K; Strasburger, Christian J.; Wu, Zida

doi:10.1210/jc.2010-2680

Cited by 79 publications

(61 citation statements)

References 28 publications

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“…This lack of relation between circulating levels of the two thyroid metabolites was also observed in the same study with a separate cohort of T4 substituted patients with pituitary insufficiency. T1AM levels were not altered following subsequent decrease in T4 levels due to supplement withdrawal in these patients [14]. These findings seem contrast to Hachenmueller et al [13] mouse model of hypothyroidism which resulted in decreased T1AM levels.…”

Section: Production and Regulationcontrasting

confidence: 66%

“…Thyroid cancer patients receiving TSH-suppressive LT4 therapy had significantly higher T1AM levels than healthy controls, but no correlation was observed between T1AM and either T4 and TSH serum levels [14]. Due to surgery, radiotherapy, or a combination of both, these patients no longer possessed any functional thyroid tissue, but their T1AM levels remained intact, suggesting an extra thyroid origin of T1AM production.…”

Section: Production and Regulationmentioning

confidence: 85%

“…This same study failed to demonstrate production of T1AM in situ with perfused rat hearts incubated with T4 [15]. Without the exact knowledge of how and where it is produced, coupled with an apparent lack of relationship between T1AM circulating thyroid hormone levels [14], it is not clear how the production and secretion of T1AM is regulated or from which tissues it is produced in. To date, there has not been any endogenous compounds identified that demonstrate the ability to increase T1AM levels nor it is known whether chronic T1AM supplementation decreases endogenous production.…”

Section: Production and Regulationmentioning

confidence: 96%

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3-Iodothyronamine: A High Potency Metabolic Hormone and its Potential for Therapeutic Applications

Rogowski¹,

Assadi‐Porter

2015

JED

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Open Access Review Articlegreater potency and receptor affinity than other thyronamines [1]. Production and regulationDue to their structural similarities, it was initially hypothesized that T1AM was derived from thyroxine (T4), accomplished through a series of one decarboxylation and three deiodination enzymatic reactions [9]. This conversion of T4 or Triiodothyronine (T3) into T1AM has not been directly demonstrated (Figure 1). It is still an attractive hypothesis for a number of reasons. Decarboxylation and deiodination are known to play an important role in thyroid hormone catabolism [10]. Thyronamines are also able to serve as substrates for deiodinases [11]. This reaction series could explain a functional role of reverse Triiodothyronine (rT3) as an intermediate product of T1AM synthesis, as rT3 is the inactive deiodination product of T4 with no known physiological function, yet it is produced in equal ratios to the active compound T3 [12]. The essential decarboxylation reaction however has not been biologically characterized, as synthesis of thyronamines from T4 or T3 would require decarboxylation to occur prior to deamination, as the amine group is retained in thyronamines. This reaction order is not usually thought to occur in thyroid hormone catabolism, but the enzyme that catalyzes this reaction, named aromatic amino acid decarboxylase, is widely expressed and possesses a broad range of substrate specificity. Though this series of reactions seems highly plausible, a more recent study using heavy isotope tracing of exogenous T4 in a mouse model of induced hypothyroidism did not demonstrate any conversion of T4 to T1AM [13]. As a result of induced hypothyroidism, T1AM levels were greatly diminished as well, but exogenous T4 administration was not able to replenish serum T1AM levels despite successfully restoring circulating T4 and T3 concentrations. This suggests that production of T1AM uses the same biosynthetic factors required for the synthesis of T4 and provides with the possibility that, T1AM is synthesized de novo in a divergent manner from that of T4. Abstract3-Iodothyronamide (T1AM) is a naturally produced endogenous hormone like molecule. Only recently it has been discovered in the past decade, the proceeding body of research emerging from its initial discovery has revealed a substantial capacity of T1AM as a new potential hormone that affects numerous physiological processes and organs. Initially, it was hypothesized to be a byproduct of Thyroid Hormone (TH) metabolism; however, the current body of evidence suggests that its production and physiological function appear to be uncoupled and dramatically divergent from that of TH. This review summarizes the physiological and biochemical effects of T1AM reported in the literature along with its proposed mechanisms of action and production pathways. The physiological effects of T1AM appear to be dose specific, in some cases exerting opposing effects in the same biological processes. Uptake, storage, and degree of effect appear to be tissue specific...

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Section: Production and Regulationcontrasting

confidence: 66%

Section: Production and Regulationmentioning

confidence: 85%

Section: Production and Regulationmentioning

confidence: 96%

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3-Iodothyronamine: A High Potency Metabolic Hormone and its Potential for Therapeutic Applications

Rogowski¹,

Assadi‐Porter

2015

JED

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“…Using an LC/MS/MS approach, Saba et al (9) reported high tissue concentrations of T 1 AM but very low serum concentrations, on the order of 0.3 nM. In contrast, Hoefig et al (10) measured substantially higher serum T 1 AM concentrations averaging ϳ66 nM using an immunoassay based on a monoclonal antibody that selectively binds T 1 AM. This immunoassay did not involve the use of an extraction procedure for isolating biogenic amines from the serum matrix, whereas all LC/MS/MS-based approaches involve some kind of a chemical extraction step.…”

Section: Discussionmentioning

confidence: 99%

“…Quantitative analysis of T 1 AM levels in rat using liquid chromatography coupled to tandem mass spectrometry (LC/MS/ MS) revealed that tissue concentrations of T 1 AM are substantially higher than serum concentrations, and in certain tissues, such as the liver, T 1 AM is present at significantly higher levels than T 4 and T 3 (9). However, human sera analyzed with a recently developed highly selective T 1 AM immunoassay demonstrated T 1 AM levels comparable with those of total circulating T 4 (10).…”

mentioning

confidence: 99%

ApoB-100-containing Lipoproteins Are Major Carriers of 3-Iodothyronamine in Circulation

Roy

Placzek

Scanlan

2012

Journal of Biological Chemistry

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3-Iodothyronamine (T 1 AM) is a biogenic amine derivative of thyroid hormone present in tissue and blood of vertebrates. Approximately 99% of the circulating thyroid hormones are bound to plasma proteins, including three major thyroid hormone-binding proteins, and the question arises as to whether circulating T 1 AM is also bound to serum factors. We report here that T 1 AM is largely bound to a single protein component of human serum. Using T 1 AM-affinity chromatography, we isolated this protein, and sequence analysis identified it as apolipoprotein B-100 (apoB-100), the protein component of several low density lipoprotein particles. Consistent with this finding, we demonstrate that >90% of specifically bound T 1 AM in human serum resides in the apoB-100-containing low density lipoprotein fraction. T 1 AM reversibly binds to apoB-100-containing lipoprotein particles with an equilibrium dissociation constant (K D ) of 17 nM and a T 1 AM/apoB-100 stoichiometry of 1:1. Competition binding assays demonstrate that this binding site is highly selective for T 1 AM. Intracellular T 1 AM uptake is significantly enhanced by apoB-100-containing lipoprotein particles. Modest enhancements to apoB-100 cellular uptake and secretion by T 1 AM were observed; however, multidose T 1 AM treatment did not affect lipid or lipoprotein inventory in vivo. Thus, it appears that apoB-100 serves as a carrier of circulating T 1 AM and affords a novel mechanism by which T 1 AM gains entry to cells.

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Uptake of 3‐iodothyronamine hormone analogs inhibits the growth and viability of cancer cells

et al. 2017

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3‐Iodothyronamine (T1AM) is a structural analog of thyroid hormone that has been demonstrated to have potent affects on numerous physiological systems. Most studies on T1AM have explored its effects in healthy functional systems; while its potential therapeutic uses and safety, and efficacy in pathological conditions are largely unknown. We sought to evaluate the effects of T1AM and its structural analog SG‐2 on cancer cell growth and viability. We analyzed the cytotoxicity of these analogs on MCF7 breast cancer cells, HepG2 hepatocellular cancer cells as well as normal control cells using primary human foreskin fibroblasts and mouse preadipocytes control cells. The cytotoxicity of T1AM and SG‐2 was determined by cell growth curves, and validated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide cell viability assays. Cellular uptake analysis was conducted using confocal microscopy. Real‐time (RT)‐PCR was conducted to identify gene pathways affected by SG‐2 in cancer cells. The IC50 of T1AM was approximately double the concentration of its analog SG‐2 in cancer cells. Cytotoxicity studies on normal cells revealed that IC50 concentrations of SG‐2 in cancer cells had no significant impact on cell viability in these cell types. Cell‐imaging experiments demonstrated rapid uptake and localization to the mitochondrial membrane. T1AM and SG‐2 are able to reduce cancer cell growth and viability. These findings support the potential for use of these compounds and related analogs for their antiproliferation properties in cancer cells.

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Evidence for Extrathyroidal Formation of 3-Iodothyronamine in Humans as Provided by a Novel Monoclonal Antibody-Based Chemiluminescent Serum Immunoassay

Cited by 79 publications

References 28 publications

3-Iodothyronamine: A High Potency Metabolic Hormone and its Potential for Therapeutic Applications

3-Iodothyronamine: A High Potency Metabolic Hormone and its Potential for Therapeutic Applications

ApoB-100-containing Lipoproteins Are Major Carriers of 3-Iodothyronamine in Circulation

Uptake of 3‐iodothyronamine hormone analogs inhibits the growth and viability of cancer cells

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