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

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.

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