Thyroid Hormonelike Actions of 3,3′,5′-l-Triiodothyronine and 3,3′-Diiodothyronine

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Abstract
L-Thyroxine is converted to 3,5,3′-l-triiodothyronine (T3) as well as to 3,3′,5′-l-triiodothyronine (reverse T3). One product of further deiodination is 3,3′-diiodothyronine (3,3′T2). The serum levels of reverse T3 and 3,3′T2 change considerably in various physiological and disease states. We previously found that reverse T3 and 3,3′T2 bind to the solubilized hepatic nuclear “receptors” for thyroid hormones. This led us to study binding and actions of these metabolites in cultured rat pituitary cells in which glucose consumption and growth hormone production are regulated by T3 and l-thyroxine. Reverse T3 and 3,3′T2 stimulated growth hormone production and glucose consumption and inhibited nuclear binding of radioactive T3. Either metabolite produced maximal effects that equaled those of T3, and neither inhibited the T3 response. Further, additive effects were observed when reverse T3 was combined with submaximal concentrations of T3. In serum-free and serum-containing media, concentrations of 3,3′T2 50- to 70- and 10- to 100-fold greater, respectively, than those of T3 were required for equivalent stimulations and for inhibition of nuclear binding by T3. The relative activity differences under the two conditions can be attributed to weaker serum protein binding of 3,3′T2 than T3. With cells in serum-free media, reverse T3 was a less avid competitor than 3,3′T2 for T3 binding by the nuclear receptors, and was less potent than 3,3′T2 (0.001 the potency of T3) in inducing growth hormone production or glucose oxidation. In incubations with serum-containing media, reverse T3 was an ineffective competitor for T3 binding, and had only 0.1 the inducing potency of 3,3′T2 (0.001 the potency of T3). The weaker activity of reverse T3 relative to 3,3′T2 in serum-containing media could be explained by stronger serum binding of reverse T3 than 3,3′T2. In addition, after long-term incubation of cells with radioactive reverse T3, much of the cell-associated radioactivity was recovered as 3,3′T2. These studies suggest that reverse T3 and 3,3′T2 can stimulate thyroid hormone-regulated functions as weak agonists by acting via the same receptors that mediate T3 actions. Moreover, some of the effects of reverse T3 may be due to 3,3′T2 produced by deiodination of reverse T3.