Tissue Distribution and Cardiac Metabolism of 3-Iodothyronamine

3-Iodothyronamine (T(1)AM) 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 T(1)AM, including a negative inotropic and chronotropic effect in cardiac preparations. This work was aimed at estimating endogenous T(1)AM concentration in different tissues and determining its cardiac metabolism. A novel HPLC tandem mass spectrometry assay was developed, allowing detection of T(1)AM, thyronamine, 3-iodothyroacetic acid, and thyroacetic acid. T(1)AM 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. T(1)AM was also identified for the first time in human blood. In H9c2 cardiomyocytes and isolated perfused rat hearts, significant Na+-dependent uptake of exogenous T(1)AM was observed, and at the steady state total cellular or tissue T(1)AM concentration exceeded extracellular concentration by more than 20-fold. In both preparations T(1)AM underwent oxidative deamination to 3-iodothyroacetic acid. T(1)AM 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 T(1)AM production was observed in cardiomyocytes exposed to exogenous thyroid hormone, although the activity of this pathway was very low. (Endocrinology 151: 5063-5073, 2010)