Thyroxine: its biosynthesis and its immunochemistry

Abstract

The suggestion that thyroxine might be formed in nature from tyrosine through the stage of diiodotyrosine was made at an early stage of the elucidation of the chemistry of thyroxine, and was made more probable when the constitution of the latter was finally determined. Over a number of years several pieces of evidence, all indirect in character, were brought forward in support of this biogenetic hypothesis which thus came to be generally accepted. Recently two lines of direct evidence have become available which seem to place the matter beyond doubt. In the first place the transformation of diiodotyrosine into thyroxine has been effected by purely chemical methods of a character which make it possible to formulate a theory of the chemistry of the process involved. Secondly, by the application of modern biochemical technique, the actual synthesis of thyroxine from diiodotyrosine has been demonstrated in surviving thyroid tissue in vitro. The latter type of experiment incidentally offers an opportunity for the analytical study of the action of substances such as thiourea which inhibit thyroid activity supposedly by interfering with the biosynthesis of the hormone. Accepting the mechanism of biosynthesis of thyroxine as being satisfactorily established we are left with two outstanding problems. Is thyroxine itself the actual circulating thyroid hormone, and if so, by what mechanism does it exercise its effect in the periphery? To the second of these questions no answer can yet be given. Evidence regarding the first is conflicting and in the attempt to obtain a definitive answer an approach has been made along a new line which raises matters of some general interest. The method is based on the theory, deduced from the known facts of immunological chemistry, that an antigen of which the determinant group is a physiologically active substance should give rise to an antiserum capable of inhibiting the characteristic activity of this substance. Application of this idea to the problem of thyroxine involved the development of a new technique for building up artificial antigenic complexes. Such a complex containing thyroxine as the determinant group has proved to be able to give rise to an antiserum which can inhibit the physiological action both of a protein containing thyroxine, such as thyroglobulin, and of thyroxine itself. The latter observation, together with extension of the experimental method to an entirely different compound, favours the hypothesis that thyroxine itself is in fact the actual circulating thyroid hormone.