Effect of Alterations in Thyroid Status on the Metabolism of Thyroxine and Triiodothyronine by Rat Pituitary Gland In Vitro

Michiko Maeda; Sidney H. Ingbar

doi:10.1172/JCI110519

The metabolism of thyroxine (T₄) was studied in slices of rat pituitary gland and liver from the same animal incubated in vitro with [¹²⁵I]T₄ and 10 mM dithiothreitol. In the pituitary gland, generation of ¹²⁵I-labeled 3,5,3′-triiodothyronine (T₃), as well as overall T₄ degradation, increased significantly at 24 h after thyroidectomy and by 2 wk were approximately five times control values. Conversely, following a single injection of T₃ (1.5 μg/100 g body wt), values for both functions were significantly decreased at 4 h, and reached a nadir of ∼20% of control values at 12 and 24 h. Net T₃-neogenesis accounted for ∼70% of T₄ degradation in control pituitaries from intact rats. This proportion was increased by thyroidectomy and decreased by T₃ replacement. Indirect evidence indicated that thyroidectomy decreased, and T₃ administration increased, non-T₃ generating pathways of T₄ metabolism, probably 5-monodeiodination leading to formation of 3,3′5′-triiodothyronine (rT₃). As judged from studies by others, the prompt changes in T₄ metabolism that followed thyroidectomy or T₃ administration could not be explained by changes in pituitary cell type. Changes in T₃-neogenesis in liver were the converse of those in pituitary, and were much slower to occur.

In the thyroidectomized rat, administration of cycloheximide resulted in an ∼60% inhibition of pituitary T₃-neogenesis and T₄-degradation at 4 h, a time-course of inhibition similar to that produced by T₃. Unlike T₃, cycloheximide did not alter the proportion of T₄ degradation that could be accounted for by T₃ neogenesis, and appeared, therefore, to inhibit both T₃ generating and non-T₃ generating pathways. The time-course of the inhibitory effect of cycloheximide on the incorporation of [³H]leucine into hemipituitaries in vitro was parallel to its effect on T₃-neogenesis. The inhibition of T₃-neogenesis that occurred when T₃ and cycloheximide were given together did not exceed the effect of T₃ alone, suggesting a common mechanism of action of the two agents.

From the foregoing information, the following tentative conclusions are drawn: (a) turnover of the 5′-monodeiodinase for T₄ in rat pituitary is rapid, substantially more so than in liver; (b) thyroidectomy enhances, and T₃ inhibits, the conversion of T₄ to T₃ in the pituitary; these manipulations have opposite effecs on the non-T₃ generating pathways of T₄ metabolism, probably the 5-monodeiodination of T₄ that produces rT₃; (c) these changes are probably the result of parallel effects on the synthesis of the corresponding enzymes; (d) the changes in T₃-neogenesis described may permit an intrapituitary feedback mechanism that damps the changes in TSH secretion mediated by classical feedback regulatory control; (e) the effects of hypothyroidism and T₃-replacement on T₃-neogenesis and overall T₄ degradation in liver were opposite to those produced in the pituitary. Hence, among differing tissues, the same stimuli may produce greatly different responses in pathways of peripheral T₄ metabolism, thus making possible differing metabolic sequelae within each.