Tissue Distribution and Cardiac Metabolism of 3-Iodothyronamine

Abstract

3-iodothyronamine (T1AM) is a novel relative of thyroid hormone, able to interact with specific G protein-coupled receptors, known as trace amine-associated receptors. Significant functional effects are produced by exogenous T1AM, including a negative inotropic and chronotropic effect in cardiac preparations. This work was aimed at estimating endogenous T1AM concentration in different tissues and determining its cardiac metabolism. A novel HPLC tandem mass spectrometry assay was developed, allowing detection of T1AM, thyronamine, 3-iodothyroacetic acid, and thyroacetic acid. T1AM was detected in rat serum, at the concentration of 0.3±0.03 pmol/ml, and in all tested organs (heart, liver, kidney, skeletal muscle, stomach, lung, and brain), at concentrations significantly higher than the serum concentration, ranging from 5.6±1.5 pmol/g in lung to 92.9±28.5 pmol/g in liver. T1AM was also identified for the first time in human blood. In H9c2 cardiomyocytes and isolated perfused rat hearts, significant Na+-dependent uptake of exogenous T1AM was observed, and at the steady state total cellular or tissue T1AM concentration exceeded extracellular concentration by more than 20-fold. In both preparations T1AM underwent oxidative deamination to 3-iodothyroacetic acid. T1AM deamination was inhibited by iproniazid but not pargyline or semicarbazide, suggesting the involvement of both monoamine oxidase and semicarbazide-sensitive amine oxidase. Thyronamine and thyroacetic acid were not detected in heart. Finally, evidence of T1AM production was observed in cardiomyocytes exposed to exogenous thyroid hormone, although the activity of this pathway was very low.

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

“…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.…”

“…T 1 AM has been detected in rodent brain, heart, and liver tissues and also in circulation of mice, guinea pigs, and Siberian hamsters (2,6,8). 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).…”

3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors

“…human and rodents (Galli et al, 2012) (Saba et al, 2010). T1AM is produced in the thyroid as well as in extra-thyroid tissues (Hoefig et al, 2012) (Hoefig et al, 2015) and is rapidly metabolized by monoamine oxidases (MAO) and deiodinase activities to 3-iodothyroacetic acid (TA1) and iodothyronamine, respectively (Hackenmueller et al, 2012).…”

In the brain of mice, 3-iodothyronamine (T1AM) is converted into 3-iodothyroacetic acid (TA1) and it is included within the signaling network connecting thyroid hormone metabolites with histamine

“…T1AM circulates in healthy rodents and is accumulated in most tissues, including the brain, where TA1 was also detected (Saba et al, 2010;Musilli et al, 2014). T1AM also circulates in humans and its levels were found to be higher in diabetic patients (Galli et al, 2012).…”