Hones et al. have recently shown that in vivo interference with the apparatus of the nuclear receptor-mediated, gene-driven mechanism of triiodothyronine (T3) actions fails to eliminate all actions of T3. However, the investigators conducting that study provided little information regarding the mechanisms that might be responsible for conferring those implied gene-independent effects. Dratman has long ago suggested a system wherein such gene-free mechanisms might operate. Therefore, since news of that discovery was originally published in 1974, it seems appropriate to describe the progress made since then. We propose that thyroxine and triiodothyronine have many different structural properties that may confer a series of different capabilities on their functions. These conform with our proposal that a series of catecholamine analogs and their conversion to iodothyronamines, allows them to perform many of the functions that previously were attributed to nuclear receptors regulating gene expression. The actions of deiodinases and the differential distribution of iodine substituents are among the critical factors that allow catecholamine analogs to change their effects into ones that either activate their targets or block them. They do this by using two different deiodinases to vary the position of an iodide ion on the diphenylether backbones of thyroxine metabolites. A panoply of these structural features imparts major unique functional properties on the behavior of vertebrates in general and possibly on Homo sapiens in particular.
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