MODULATION OF TOXIN INJURY BY HYPO/HYPER THYROIDISM

甲状腺激素（T4和T3）水平过高或不足， 与麻醉剂肝毒性的改变有关， 毒品和其他化学品。 人们对原因知之甚少 负责化学调节的效应关系 甲状腺功能不全的危害 拟议的研究将 研究两种可能的机制， T4状态过多或不足引起的化学性肝损伤：1） 有毒代谢物形成或解毒的相对速率 和2）T4诱导的线粒体的变化， 功能改变线粒体对损伤的易感性。 1，1-二氯乙烯（DCE）在进食雄性大鼠中的肝毒性是 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代谢为“有害” 通过II相反应代谢产物并通过II相反应解毒 DCE引起线粒体早期损伤 其功能被甲状腺激素广泛改变 功能障碍 目的我将使用酶分析，电子显微镜和 组织化学以确定-T4中DCE损伤的程度， +T4大鼠与正常甲状腺功能正常大鼠相比，特别是 关于线粒体损伤。 目标2将使用GC、HPLC和 14 C-DCE，以确定DCE代谢的相对速率， I相和II相反应在-T4中改变不同， +T4大鼠，导致减少或增强“伤害性”共价 与细胞成分结合。 目标3将检验以下假设： -T4和+T4大鼠线粒体关键酶活性 受DCE的影响不同，ATP发生相关变化 程度. 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大鼠的损伤对DCE代谢产物有直接影响 形成或解毒。 我的长期目标是 了解诱导或改变细胞的细胞变化 通过将细胞结构改变与功能改变相关联来损伤 选民。 拟议的研究将通过以下方式推进这一目标： 提供有关激素诱导变化的新信息 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.