Thyroid Hormone Interactions: Molecular Conformation, Protein Binding, and Hormone Action*

STUDIES of the thyroid hormones (Fig. 1) continue to provide new insights into the molecular level events controlling biosynthesis, transport, and mechanism of action. Despite the progress made in understanding thyroid hormone effects on specific metabolic reactions, there is as yet no unifying concept describing thyroid hormone function. However, it has been shown that the thyroid hormones have profound effects on growth, differentiation, and development of tissues, as well as effects on carbohydrates, proteins, and lipids. Since the thyroid hormones are protein bound when transported throughout the general circulation, when at the cell membrane, and when in the cell nucleus, their molecular level interactions with these proteins are of paramount interest. This suggests that the stereochemical nature of the hormones plays an important role in defining thyroid hormone activity. Only the thyroid hormones T4 and T3, synthesized in the thyroid gland, are secreted into the blood stream in response to thyroid stimulating hormone. However, with the advent of more sensitive radioimmunoassay techniques (1), the presence of all the deiodination products of thyroxine (Fig. 2) was identified in the thyroid gland. As yet, the physiological function of these metabolites is not known. It has been shown that almost all of the circulating T3 is generated peripherally from T4. Reverse T3 (3,3′,5′-triiodothyronine), which comes from the deiodination of the inner ring of thyroxine (Fig. 2), as opposed to outer ring deiodination to form T3, has also been identified in the plasma but is not physiologically active. It has been suggested that the selective deiodination of T4 may represent an important peripheral regulatory mechanism for modulating the quantity of biologically active hormone at the tissue level (2).