Incorporating Thyronamines into Thyroid Hormone Metabolism

描述（由申请方提供）：需要对甲状腺激素代谢进行有针对性的研究，因为最近发现了内源性甲状腺原氨酸（甲状腺激素的一种可能代谢物），其具有与过量甲状腺激素相反的深刻生理效应。为了开始研究涉及甲状腺原氨酸的途径，本研究建议背后的假设是a）甲状腺原氨酸是甲状腺素的代谢物，B）生物活性甲状腺乙酸是由相应的甲状腺原氨酸形成的。由于含碘化合物仅由甲状腺产生，因此这些结构相似的代谢物来源于甲状腺素并可通过已知的生物转化产生是合理的。为了能够证明3-碘甲状腺原氨酸是由甲状腺素形成的，需要合成[3，5 - 125l]-甲状腺素（具体目标1）。该化合物和[3'，5'-125l]-甲状腺素将允许在这些放射性标记化合物与大鼠肝细胞孵育后检测到任何碘甲状腺原氨酸。所提出的转化酶存在于肝脏中。胺提取，然后对产物进行色谱分离，并与不同的甲状腺原氨酸进行比较，以鉴别已形成的任何碘甲状腺原氨酸（具体目标2）。为了确定甲状腺乙酸是由甲状腺原氨酸形成的，将用大鼠肝细胞研究3，5，[1251 - 3']-三碘甲状腺原氨酸（具体目标1中的合成）向3，5，[1251 - 3']-三碘甲状腺乙酸的体外转化。同样，所提出的转化酶存在于肝脏中。将进行羧酸提取，然后对产物进行色谱分离，并与三碘甲状腺乙酸和其他碘甲状腺乙酸进行比较（具体目标3）。这项工作是有意义的，因为它将提供证据支持的模型，甲状腺素可以代谢成两种不同的化合物，具有相反的生理作用，特别是3，5，3'-三碘甲状腺原氨酸和甲状腺胺。如果这个模型是正确的，这将是一个优雅的方法，为身体维持稳态。此外，这项工作可以确定生物学上重要的3，5，3'-三碘甲状腺乙酸是如何形成的另一种途径。甲状腺激素及其代谢产物对脊椎动物的生长、发育和代谢都很重要。甲状腺内分泌系统的异常与许多疾病有关，如癌症。进一步的工作是必要的，以阐明甲状腺素胺的作用，并确定这一途径是否涉及任何疾病。

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.