Incorporating Thyronamines into Thyroid Hormone Metabolism

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DESCRIPTION (provided by applicant): A targeted investigation of thyroid hormone metabolism is required because of the recent identification of endogenous thyronamines, a possible metabolite of thyroid hormone, with profound physiological effects that are opposite of excess thyroid hormone. To begin investigating the pathway involving thyronamines, the hypotheses behind this research proposal are a) that thyronamines are metabolites of thyroxine and b) that biologically active thyroacetic acids are formed from the corresponding thyronamines. Because iodine- containing compounds are only produced by the thyroid gland, it is reasonable that these structurally similar metabolites are derived from thyroxine and could be produced by known biological transformations. To be able to demonstrate that 3-iodothyronamine is formed from thyroxine, the synthesis of [3,5-125l]-thyroxine is required (Specific Aim 1). This compound and [3',5'-125l]-thyroxine will allow any iodothyronamine to be detected after these radiolabeled compounds have been incubated with rat hepatocytes. The enzymes for the proposed transformations are present in the liver. An amine extraction followed by chromatographic separation of products and comparison to different thyronamines will identify any iodothyronamines that have been formed (Specific Aim 2). To determine that thyroacetic acids are formed from thyronamines, the in vitro conversion of 3,5,[125l-3']-triiodothyronamine (synthesis in Specific Aim 1) to 3,5,[1251-3']- triiodothyroacetic acid will be investigated with rat hepatocytes. Again the enzymes for the proposed transformations are present in the liver. An extraction for carboxylic acids followed by chromatographic separation of the products and comparison to triiodothyroacetic acid and other iodothyroacetic acids will be performed (Specific Aim 3). This work is significant because it will provide evidence to support the model that thyroxine can be metabolized into two different compounds with opposing physiological effects, specifically 3,5,3'-triiodothyronine and thyronamines. If this model is correct, it would be an elegant method for the body to maintain homeostasis. Also this work could identify another pathway for how the biologically important 3,5,3'-triiodothyroacetic acid is formed. Thyroid hormone and its metabolites are important for vertebrate growth, development, and metabolism. Abnormalities with the thyroid endocrine systems are associated with many disorders and diseases, such as cancer. Further work is necessary to elucidate the role of thyronamines and determine whether this pathway is involved in any diseases.