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.
