Incorporating Thyronamines into Thyroid Hormone Metabolism

描述（由申请人提供）：由于最近发现了内源性甲状腺胺，这是一种可能的甲状腺激素代谢物，具有与过量甲状腺激素相反的深刻生理作用，因此需要对甲状腺激素代谢进行有针对性的研究。为了开始研究涉及甲状腺胺的途径，本研究提案背后的假设是：a)甲状腺胺是甲状腺素的代谢物；b)相应的甲状腺胺形成具有生物活性的甲状腺乙酸。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。为了证明3-碘甲状腺胺是由甲状腺素形成的，需要合成[3,5-125l]-甲状腺素（Specific Aim 1）。该化合物和[3',5'-125l]-甲状腺素在这些放射性标记的化合物与大鼠肝细胞孵育后可以检测到任何碘甲状腺胺。所提出的转化的酶存在于肝脏中。胺提取，然后是色谱分离产物和与不同甲状腺胺的比较，将确定已形成的任何碘甲状腺胺（特定目的2）。为了确定甲状腺素胺是否形成甲状腺素乙酸，我们将在大鼠肝细胞中研究3,5,[125l-3']-三碘甲状腺素胺（在Specific Aim 1中合成）向3,5,[1253 -3']-三碘甲状腺素乙酸的体外转化。再次提出的转化酶存在于肝脏中。提取羧酸，然后对产物进行色谱分离，并与三碘甲状乙酸和其他碘甲状乙酸进行比较（具体目的3）。这项工作具有重要意义，因为它将提供证据支持甲状腺素可以代谢成两种具有相反生理作用的不同化合物的模型，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，它将是身体维持体内平衡的一种优雅的方法。此外，这项工作还可以确定另一种途径，了解具有重要生物学意义的3,5,3'-三碘甲状腺乙酸是如何形成的。甲状腺激素及其代谢物对脊椎动物的生长、发育和代谢具有重要作用。甲状腺内分泌系统的异常与许多紊乱和疾病有关，如癌症。需要进一步的工作来阐明甲状腺胺的作用，并确定这一途径是否与任何疾病有关。

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.