MODULATION OF TOXIN INJURY BY HYPO/HYPER THYROIDISM

甲状腺功能减退/亢进对毒素损伤的调节

• 批准号: 3465126
• 负责人: MARY F KANZ
• 金额: $ 7.97万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 1991-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3465126
• 关键词: NAD(H) phosphate; adenosine diphosphate; adenosine triphosphate; covalent bond; detoxification; electron microscopy; enzyme mechanism; fluorimetry; gas chromatography; glutathione; hepatotoxin; high performance liquid chromatography; hormone regulation /control mechanism; hyperthyroidism; hypothyroidism; laboratory rat; liver metabolism; liver toxic disorder; microscopy; mitochondrial membrane; oxidative phosphorylation; oxygen microelectrode; polarography; radioimmunoassay; scintillation counter; thyroidectomy; thyroxine; toxicant interaction; toxin metabolism; vinyledene chloride

Excess or deficient thyroid hormone (T4 and T3) levels are associated with alterations in the hepatotoxicity of anesthetics, drugs and other chemicals. Very little is known about the cause effect relationships responsible for the modulation of chemical injury during thyroid dysfunction. The proposed research will investigate two possible mechanisms for the modification of chemical liver injury by excess or deficient T4 status: 1) that relative rates of toxic metabolite formation or detoxification are modified and 2) that the T4-induced changes in mitochondrial function alter mitochondrial susceptibility to injury. Hepatotoxicity of 1,1-dichloroethylene (DCE) in fed, male rats is a particularly suitable model of these studies because 1: hypothyroidism (-T4) decreases while hyperthyroidism (+T4) potentiates DCE toxicity; 2) DCE is metabolized to "injurious" metabolites by phase II reactions and detoxified by phase II reactions; and 3) DCE produces early injury of mitochondria whose function is extensively altered by thyroid hormone dysfunction. Aim I will use enzyme assays, electron microscopy and histochemistry to establish the degree of DCE injury in -T4 and +T4 rats compared to normal euthyroid rats, particularly with regard to mitochondrial injury. Aim 2 will use GC, HPLC and 14C-DCE to determine if relative rates of DCE metabolism by phase I and phase II reactions are altered differently in -T4 and +T4 rats, resulting in reduced or enhanced "injurious" covalent binding to cell constituents. Aim 3 will test the hypothesis that activities of critical mitochondrial enzymes in -T4 and +T4 rats are differentially affected by DCE with related changes in ATP levels. Aim 4 will test the hypothesis that acute increases in mitochondrial oxidative phosphorylation will produce greater injury in -T4 rats with direct effects on DCE metabolite formation or detoxification. My long-term objective is to understand the cellular changes which induce or modify cell injury by correlating structural to functional alterations in cell constituents. The proposed studies will further this goal by providing new information on how hormonally-induced changes can modulate the liver's response to chemical toxin.

甲状腺激素（T4 和 T3）水平过多或不足 与麻醉剂肝毒性的改变有关， 药物和其他化学品。 对于其原因知之甚少 负责化学调节的效应关系 甲状腺功能障碍期间的损伤。 拟议的研究将 研究两种可能的修饰机制 T4 状态过多或不足导致化学性肝损伤：1) 有毒代谢物形成或解毒的相对速率 被修改，2）T4 诱导的线粒体变化 功能改变线粒体对损伤的易感性。 1,1-二氯乙烯 (DCE) 对喂养的雄性大鼠的肝毒性 这些研究的一个特别合适的模型，因为 1： 甲状腺功能减退 (-T4) 降低，而甲状腺功能亢进 (+T4) 增强 DCE 毒性； 2）DCE被代谢为“有害” II 相反应的代谢物和 II 相解毒 反应； 3) DCE 造成线粒体早期损伤 其功能被甲状腺激素广泛改变 功能障碍。 目标 我将使用酶测定、电子显微镜和 组织化学以确定-T4和DCE损伤的程度 +T4 大鼠与正常甲状腺正常大鼠相比，特别是 关于线粒体损伤。 目标 2 将使用 GC、HPLC 和 14C-DCE 以确定 DCE 代谢的相对速率 I 相和 II 相反应在 -T4 和 -T4 中发生不同的改变 +T4大鼠，导致“有害”共价减少或增强 与细胞成分结合。 目标 3 将检验以下假设： -T4 和 +T4 大鼠中关键线粒体酶的活性 DCE 对 ATP 的相关变化有不同的影响 水平。 目标 4 将检验以下假设： 线粒体氧化磷酸化会产生更大的 -T4 大鼠损伤对 DCE 代谢有直接影响 形成或解毒。 我的长期目标是 了解诱导或修饰细胞的细胞变化 通过将细胞的结构与功能改变相关联来造成损伤 选民。 拟议的研究将通过以下方式进一步推动这一目标 提供有关荷尔蒙如何引起变化的新信息 可以调节肝脏对化学毒素的反应。