MODULATION OF TOXIN INJURY BY HYPO/HYPER THYROIDISM

甲状腺激素(T4和T3)水平过高或不足的有 与麻醉剂肝脏毒性的改变有关， 毒品和其他化学物质。人们对其原因知之甚少 化学物质调控的效应关系 甲状腺功能障碍时的损伤。拟议的研究将 调查两种可能的修改机制 T4状态过多或不足引起的化学性肝损伤：1) 毒性代谢物形成或解毒的相对速率 和2)T4诱导的线粒体变化 功能改变线粒体对损伤的敏感性。 1，1-二氯乙烯(DCE)对饲养雄性大鼠的肝毒性 这些研究的一个特别合适的模型，因为1： 甲减(-T4)减少，甲亢(+T4)减少 增强DCE的毒性；2)DCE被代谢成“有害的” II相反应的代谢物和II相的解毒 反应；3)DCE引起线粒体的早期损伤 其功能被甲状腺激素广泛改变 功能障碍。 目的我将使用酶分析，电子显微镜和 组织化学以确定DCE在T4和T4中的损伤程度 +T4大鼠与正常甲状腺功能正常大鼠比较，尤其是 关于线粒体损伤。AIM 2将使用GC、HPLC和 14C-DCE用于确定DCE的相对代谢率是否通过 第一相和第二相反应在-T4和-T4中的变化不同 +T4大鼠，导致损伤共价降低或增强 与细胞成分结合。目标3将检验这一假设 -T4和+T4大鼠线粒体关键酶活性的变化 受到DCE的不同影响，并伴随着ATP的相关变化 级别。目标4将检验这一假设，即 线粒体氧化磷酸化将产生更大的 对DCE代谢产物有直接影响的In-T4大鼠损伤 排毒形成或排毒。我的长期目标是 了解诱导或修改细胞的细胞变化 细胞结构与功能改变相关的损伤 选民。拟议的研究将通过以下方式推动这一目标 提供关于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。

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.