Aspects of peripheral thyroid hormone metabolism

The research into thyroid function has a long history. The recognition of goiter as pathology of the thyroid gland dates back to the ancient world of Rome and Greece and possibly even to the early history of chinese medicine. In an excellent review of the historical aspects of the discovery of thyroid hormones and their biological action (1) Pitt-Rivers describes the growing awareness of the significance of iodine for thyroid function early in the 19th century. The actual presence of organic iodine in the thyroid gland was demonstrated for the first time in 1896 by Baumann who called his concentrate of a thyroid extract "Iodothyrin". In 1914 Kendall isolated a crystalline material from thyroid hydrolysates and named it "Thyroxin" after thyroxindole, since he believed this sUbstance to be an indole derivative. The compound proved to have biological activity in hypothyroid man and aninals. The actual structure fonnula of the thyroxine rrolecule was disclosed by Harington in 1926. Only in 1952 the existence of 3,3' ,5-triiodothyronine was simultaneously demonstrated in beef thyroid and human serum by Gross and Pitt-Rivers and in rat thyroid by Roche et al. At the same time it appeared that this triiodothyronine was about three times as potent as thyroxine in the goiter prevention assay in rats. The original postulate by Gross and Pitt-Rivers (1953) that triiodothyronine originates by degradation of thyroxine in peripheral tissues and constitutes the principal active thyroid hormone was established by Sterling and Braverman in as late as 1970. Since this time thyroid research has explosively expanded in many fields, such as thyroidal synthesis and secretion of iodothyronines, feedback regulations of the hypothalamic-pituitary-thyroid axis, goiter etiology and autoimmune rrechanisrns with associated hyper- and hyperthyroidism, thyroid cancer, vascular transport proteins, nuclear thyroid hormone receptors with post-receptor biological effects and the broad field of peripheral thyroid honnone rnetabolism. This last subject in its turn can be subdivided into smaller areas, such as kinetic studies with isotope labeled thyroid hormones ,the processes involved in membrane transport, as well as the subcellular distribution of either locally produced or plasma-bome iodothyronines. But also, and this represents an important section in this tllesis, the intracellular metabolism of the m.lltiple thyroxine- derived metabolites. It is obvious that the above list is far from complete, but it gives an irrpression of the wide scope of current thyroid research. This thesis is a compilation of various investigations in the field of peripheral thyroid horrrone metabolism. The rrain objective of the presented work has been to obtain rrore kno.vledge about the physiology of the various metabolic pathways of iodothyronines. This objective was chosen in the hope to contribute to a better understanding of the complex metabolic adaptations in iodothyronine :metabolism, known to be induced by several drugs, dietary changes or diseases. At first sight the rather diverse subjects of investigation in Section II of this thesis bear no apparent relation