Incorporating Thyronamines into Thyroid Hormone Metabolism

将甲状腺胺纳入甲状腺激素代谢

• 批准号: 7217149
• 负责人: WARREN J WOOD
• 金额: $ 4.47万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-08-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217149
• 关键词: acetates; amines; biotransformation; cell line; chemical synthesis; chromatography; high performance liquid chromatography; hormone metabolism; iodine; liver cells; postdoctoral investigator; thyroid hormones; thyronines; thyroxine

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.

描述(申请人提供)：由于最近发现了内源性甲状腺激素，它可能是甲状腺激素的代谢物，与过量的甲状腺激素相反，具有深刻的生理作用，因此需要对甲状腺激素代谢进行有针对性的研究。为了开始研究与甲状腺原氨酸有关的途径，这项研究计划背后的假设是：a)甲状腺原氨酸是甲状腺激素的代谢物，b)生物活性的甲状腺乙酸甲酯是由相应的甲状腺原氨酸形成的。因为含碘化合物只由甲状腺产生，所以这些结构相似的代谢物来自甲状腺激素是合理的，可以通过已知的生物转化产生。为了能够证明3-碘甲状腺原胺是由甲状腺激素形成的，需要合成[3，5-125l]-甲状腺激素(特定目标1)。这种化合物和[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胺。所提议的转化所需的酶存在于肝脏中。提取胺，然后对产物进行层析分离，并与不同的甲状腺胺进行比较，即可确定已形成的任何碘甲状腺原胺(具体目标2)。为了确定3，5，[125l-3‘]-三碘甲状腺原氨酸是由甲胺形成的，我们用大鼠肝细胞研究了3，5，[125l-3’]-三碘甲状腺原氨酸(特指合成1)到3，5，[1251-3‘]-三碘甲酸的体外转化。同样，所提议的转化所需的酶存在于肝脏中。将对羧酸进行提取，然后对产物进行层析分离，并与三碘甲酸和其他碘甲酸进行比较(具体目标3)。这项工作具有重要意义，因为它将提供证据支持甲状腺激素可以被代谢成两种不同的化合物的模型，这些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原氨酸。如果这个模型是正确的，这将是一个优雅的身体维持动态平衡的方法。此外，这项工作还可以确定具有重要生物学意义的3，5，3‘-三碘甲酸如何形成的另一条途径。甲状腺激素及其代谢产物对脊椎动物的生长、发育和代谢具有重要作用。甲状腺内分泌系统的异常与许多疾病和疾病有关，如癌症。需要进一步的工作来阐明甲状腺原氨酸的作用，并确定这一途径是否与任何疾病有关。