Effect of alterations in thyroid status on the metabolism of thyroxine and triiodothyronine by rat pituitary gland in vitro.
The metabolism of thyroxine (T(4)) was studied in slices of rat pituitary gland and liver from the same animal incubated in vitro with [(125)I]T(4) and 10 mM dithiothreitol. In the pituitary gland, generation of (125)I-labeled 3,5,3'-triiodothyronine (T(3)), as well as overall T(4) degradation, increased significantly at 24 h after thyroidectomy and by 2 wk were approximately five times control values. Conversely, following a single injection of T(3) (1.5 mug/100 g body wt), values for both functions were significantly decreased at 4 h, and reached a nadir of approximately 20% of control values at 12 and 24 h. Net T(3)-neogenesis accounted for approximately 70% of T(4) degradation in control pituitaries from intact rats. This proportion was increased by thyroidectomy and decreased by T(3) replacement. Indirect evidence indicated that thyroidectomy decreased, and T(3) administration increased, non-T(3) generating pathways of T(4) metabolism, probably 5-monodeiodination leading to formation of 3,3'5'-triiodothyronine (rT(3)). As judged from studies by others, the prompt changes in T(4) metabolism that followed thyroidectomy or T(3) administration could not be explained by changes in pituitary cell type. Changes in T(3)-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 approximately 60% inhibition of pituitary T(3)-neogenesis and T(4)-degradation at 4 h, a time-course of inhibition similar to that produced by T(3). Unlike T(3), cycloheximide did not alter the proportion of T(4) degradation that could be accounted for by T(3) neogenesis, and appeared, therefore, to inhibit both T(3) generating and non-T(3) generating pathways. The time-course of the inhibitory effect of cycloheximide on the incorporation of [(3)H]leucine into hemipituitaries in vitro was parallel to its effect on T(3)-neogenesis. The inhibition of T(3)-neogenesis that occurred when T(3) and cycloheximide were given together did not exceed the effect of T(3) 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 T(4) in rat pituitary is rapid, substantially more so than in liver; (b) thyroidectomy enhances, and T(3) inhibits, the conversion of T(4) to T(3) in the pituitary; these manipulations have opposite effecs on the non-T(3) generating pathways of T(4) metabolism, probably the 5-monodeiodination of T(4) that produces rT(3); (c) these changes are probably the result of parallel effects on the synthesis of the corresponding enzymes; (d) the changes in T(3)-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 T(3)-replacement on T(3)-neogenesis and overall T(4) 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 T(4) metabolism, thus making possible differing metabolic sequelae within each.
D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology; D006980:Hyperthyroidism / Q000378:metabolism*; D007037:Hypothyroidism / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D010902:Pituitary Gland / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains / Q000378:metabolism; D013974:Thyroxine / Q000378:metabolism* / Q000494:pharmacology; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology
D014284:Triiodothyronine; D003520:Cyclophosphamide; D013974:Thyroxine