The broad aim of this research program is to elucidate basic mechanisms in selected areas of thyroid biochemistry, physiology, and pharmacology. The major areas to be investigated are: l. The source of hydrogen peroxide in the thyroid. Elucidation of the biochemical pathway for H2O2 formation remains one of the major unsolved problems in thyroid research. It is likely that many disorders of thyroid function in humans involve underproduction or overproduction of H2O2. The proposed study will be performed with isolated open follicle preparations from hog thyroid tissue. We have developed a very sensitive method for measuring H2O2,, using cyt c peroxidase. Use of the open follicle system should permit correlations to be made between iodination and H2O2 generation. 2. Thyroid peroxidase-catalyzed iodination and coupling - Specificity of thyroid proxidase in iodination of thyroglobulin (Tg) required further study. The question to be addressed is: Does the peroxidase direct the iodination toward specific hormonogenic residues of Tg or is this primarily a function of the structure of Tg itself? Specific tyrosyl residues iodinated by chemical and enzymatic procedures at matched levels of iodination will be compared. Comparisons will be made between thyroid peroxidase and lactoperoxidase. Hormonogenic residues will be identified by peptide mapping. 3. Studies with iodine deficient rats - Iodine deficiency is a major nutritional problem in many areas of the world. Previous studies have suggested that T4 production is decreased much more than T3 production in severe iodine deficiency. We plan to make such measurements in severely iodine-deficient rats with a newly developed kinetic procedure based on 125I-T4 and 125I-T3 plasma disappearance curves. The effect of severe iodine deficiency on peripheral T4 to T3 conversion will also be measured. 4. Studies with antithyroid compounds - Further studies on intrathroidal metabolites of thioureylene drugs will be performed. These are clinically used drugs, and it is important to understand how they are metabolized in their primary target organ. 35S- and 14C-labeled compounds will be used in conjunction with HPLC. 5. Thyroid lysosomes and Tg proteolysis - Improvements have been made in this laboratory in separating primary and secondary lysosomes of the thyroid. These will be applied to elucidate mechanisms of lysosomal digestion of Tg. Patterns of lysosomal and pronase digestion will be compared.
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