The many faces of thyroxine.

Hönes 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.

3-Monoiodothyronamine: the rationale for its action as an endogenous adrenergic-blocking neuromodulator.

The investigations reported here were designed to gain insights into the role of 3-monoiodothyronamine (T1AM) in the brain, where the amine was originally identified and characterized. Extensive deiodinase studies indicated that T1AM was derived from the T4 metabolite, reverse triiodothyronine (revT3), while functional studies provided well-confirmed evidence that T1AM has strong adrenergic-blocking effects. Because a state of adrenergic overactivity prevails when triiodothyronine (T3) concentrations become excessive, the possibility that T3's metabolic partner, revT3, might give rise to an antagonist of those T3 actions was thought to be reasonable. All T1AM studies thus far have required use of pharmacological doses. Therefore we considered that choosing a physiological site of action was a priority and focused on the locus coeruleus (LC), the major noradrenergic control center in the brain. Site-directed injections of T1AM into the LC elicited a significant, dose-dependent neuronal firing rate change in a subset of adrenergic neurons with an EC(50)=2.7 microM, a dose well within the physiological range. Further evidence for its physiological actions came from autoradiographic images obtained following intravenous carrier-free (125)I-labeled T1AM injection. These showed that the amine bound with high affinity to the LC and to other selected brain nuclei, each of which is both an LC target and a known T3 binding site. This new evidence points to a physiological role for T1AM as an endogenous adrenergic-blocking neuromodulator in the central noradrenergic system.

Imaging triiodothyronine binding kinetics in rat brain: a model for studies in human subjects.

Many lines of evidence indicate a role for thyroid hormones in the expression of cognitive and affective disorders. These conditions constitute a large proportion of the illness burden in the general population. Unfortunately, presently available diagnostic procedures cannot adequately identify these problems. To determine whether imaging studies of thyroid hormone kinetics in brain might be feasible in patients with these disorders, an autoradiographic method for measuring thyroid hormone kinetics was developed. Twenty-five awake adult rats received high specific activity [(125)I]-triiodothyronine (T(3)*). Brains were obtained at intervals from 5 through 300 min after i.v. hormone administration. Every 5th frozen section was thaw mounted and exposed to film. To determine whether T(3) was responsible for the autoradiographic images, the intervening sections were assembled while frozen in regional tissue pools and were extracted and then analyzed by high-performance liquid chromatography. The results demonstrated that radioactivity was almost entirely due to T(3)*( approximately 90%) while small amounts of hormone metabolites, including [(125)I]iodine accounted for the remainder. Regional concentrations of label in autoradiograms were measured by densitometry in hippocampus (CA1, CA2, CA3, and dentate gyrus), cerebellum (molecular and granular cell layers), caudate nucleus, and amygdala. Unexpectedly and interestingly, the results demonstrated that binding through 5 h was mainly irreversible. Regional values of the net uptake rate constant of T(3)* or influx constant, K(i), were determined from the time course of the T(3)* data, showing significant differences among regions. These results suggest that imaging of labeled thyroid hormone ligands by positron emission tomography or single photon emission computed tomography may be feasible and would potentially provide useful information relevant to T(3) processing in the brain during a variety of drug and disease-induced conditions.