Date

May 2012

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Physiology and Pharmacology

Institution

Oregon Health & Science University

Abstract

3-Iodothyronamine (T[subscript 1]AM) is an endogenous derivative of thyroid hormone with a unique pharmacological profile. T[subscript 1]AM acutely induces hypothermia in rodents, decreases cardiac function, and alters fuel utilization. These actions are opposite those typically associated with thyroid hormone and suggest that T[subscript 1]AM may play a role in regulating thyroid hormone action. Structural similarities between T[subscript 1]AM and thyroid hormone include a core biaryl ether carbon structure and the presence of iodine, but thyroid hormone contains an amino acid side chain while T[subscript 1]AM has an ethylamine side chain. In vitro, T[subscript 1]AM is a substrate for metabolism by similar pathways to those that metabolize thyroid hormone, including glucuronidation and sulfation. Oxidative deamination of T[subscript 1]AM and higher iodothyronamines also produce thyroacetic acids, known metabolites of thyroid hormone, in vitro and in vivo. The similarities in structure and metabolism between T[subscript 1]AM and thyroid hormone have led to the hypothesis that T[subscript 1]AM is a decarboxylated and deiodinated metabolite of thyroid hormone. This hypothesis was tested in vivo using a stable isotope labeled thyroid hormone and a hypothyroid mouse model. Analysis by liquid chromatographytandem mass spectrometry allows for distinction between endogenous compounds and those arising from metabolism of the labeled thyroid hormone. The results indicate that T[subscript 1]AM biosynthesis is dependent on thyroid gland function, but it is not produced through extrathyroidal metabolism of thyroid hormone. The in vivo metabolism of T[subscript 1]AM was characterized following a single IP injection in mice. Using information dependent acquisition methods and liquid chromatography-tandem mass spectrometry, serum metabolites of T[subscript 1]AM were identified and quantified. Two novel compounds, N-acetyl-T[subscript 1]AM and T[subscript 1]AM-glucuronide, were identified in mouse serum. T[subscript 1]AM is also sulfated and oxidatively deaminated in mouse serum. This panel of metabolites was quantified in serum and several metabolites were present at greater concentrations than unmodified T[subscript 1]AM. This indicates that metabolism of T[subscript 1]AM is extensive, similar to the metabolism observed for thyroid hormones, and likely plays an important role in regulating the distribution and action of endogenous T[subscript 1]AM.

Identifier

doi:10.6083/M4N29TZ9

School

School of Medicine

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