Specific Triiodothyronine Binding Sites in the Anterior Pituitary of the Rat

209

A B S T R A C T Inijections of triiodothyronine (T3)and thyroxine (T4) into chronically hypothyroid rats were used to evaluate the contribution of intracellular T4 to T3 conversion to nuclear T3 in pituitary, liver, and kidney, and to correlate the occupancy of pituitary nuclear T3 receptors with inhibition of thyroid-stimulating hormone (TSH) release. Injection of a combination of 70 ng T3 and 400 ng T4/100 g body wt resulted in plasma T3 concentrations of 45+7 ng/dl (mean±+-SD) and 3.0±0.4,ug/dl T43 h later. At that plasma T3 level, the contribution of plasma T3 to the nuclear receptor sites resulted in saturation of 34±7% for pituitary, 27±5% for liver, and 33+2% for kidney. In addition to the T3 derived from plasma T3, there was additional T3 derived from intracellular monodeiodination of T4 in all three tissues that resulted in total nuclear occuipancy (as percent saturation) of 58±11% (pituitary), 36±8% (liver), and 41+11% (kidney), respectively. The percent contribution of T3 derived from cellular T4 added 41% of the total nuclear T3 in the pituitary which was significantly higher than the contribution of this source in the liver (24%) or the kidney (19%). 3 h after intravenous injection of increasing doses of T3, the plasma T3 concentration correlated well with both the change in TSH and the nuclear occupancy, suggesting a linear relationship between the integrated nuclear occupancy by T3 and TSH release rate. The contribution of intrapituitary T4 to T3 conversion to nuclear T, was accompanied by an appropriate decrease in TSH, supporting the biological relevance of nuclear T3. Pretreatment of the animals with 6-n-propylthiouracil before T4 injection decreased neither the nuclear T3 derived from intrapituitary T4 nor the subsequent decrease in TSH.These results indicate that intracellular monodeiodination of T4 contributes substantially to the nuclear T3 in the pituitary of the hypothyroid rat, and suggest a linear inverse relationship between nuclear receptor occupancy by T3 in the pituitary and TSH release rate. The data further indicate that T4 to T3 monodeiodination is considerably more important as a source of nuclear T3 in the pituitary than in the liver and kidney. This provides a mechanism whereby the TSH secretion could respond promptly to a decrease in thyroid secretion (predominantly T4) before a decrease in plasma T3 would be expected to lead to significant metabolic hypothyroidism. INTRODUCTIONThere is considerable indirect evidence suggesting that interaction of triiodothyronine (T3)l with a specific

Section: Methodssupporting

confidence: 80%

Section: Specific Experimetital Protocolsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Contributions of Plasma Triiodothyronine and Local Thyroxine Monodeiodination to Triiodothyronine to Nuclear Triiodothyronine Receptor Saturation in Pituitary, Liver, and Kidney of Hypothyroid Rats

Silva¹,

Larsen²

1978

209

“…If, as these studies suggest, T4 must be converted to Ts to exert its metabolic effect, feedback regulation of the thyroidpituitary-hypothalamic axis would most likely be dependent on tissue (pituitary) T3 levels. The presence of specific binding sites for T3 but not for T4 in the nuclei of pituitary cells provides further support for this concept (22). The T3 present in the pituitary could be derived either from T4 or from the thyroid gland via direct secretion.…”

Section: Discussionmentioning

confidence: 50%

Triiodothyronine and Thyroxine in the Serum and Thyroid Glands of Iodine-Deficient Rats

Abrams¹,

Larsen²

1973

153

A B S T R A C T Triiodothyronine (T3) and thyroxine (T4) were measured by immunoassay in the serum and thyroid hydrolysates of control (group A), mildly iodine-deficient (group B), and severely iodine-deficient rats (group C). These results were correlated with changes in thyroidal weight, 'I uptake and "2I content as well as with the distribution of 131I in Pronase digests of the thyroid. There was a progressive increase in thyroid weight and '1I uptake at 24 h with decrease in iodine intake. The PI content of the thyroids of the group B animals was 44% and that of the group C animals 2% of that in group A. The mean labeled monoiodotyrosine/diiodotyrosine (MIT/DIT) and T3/T4 ratios in group A were 0.42±0.07 (SD) and 0.12±0.01, 0.59±0.06 and 0.11±0.03 in group B, and 2.0±0.3 and 1.8±0.9 in the group thyroid digests.Mean serum T4 concentration in the control rats was 4.2±0.6 (SD) Ag T4/100 ml, 4.5+0.3 Ag/100 ml in group B animals, and undectectable (<0.5 tL/100 ml) in group C animals. There was no effect of iodine deficiency on serum T3 concentrations, which were 44+ 9 (Mean±SD) ng/100 ml in A animals, 48±6 ng/100 ml .n B animals, and 43+6 ng/100 ml in the C group. Thyroidal digest Ts and To concentrations were 39 and 400 ng/mg in group A animals and were reduced to 5 and 1% of this, respectively, in group C. The molar ratio of Ta/Ti in the thyroid digests of the groups A and B animals was identical to the ratio of labeled Ts/T4 and was slightly less (1.0±0.9) than the labeled T3/T ratio in the group C animals. T4/T3 ratio in the serum of each iodine-deficient animal. This analysis suggested that the labeled thyroid hormones in the severely iodine-deficient rat were secreted in the ratio in which they are present in the gland.Kinetic analysis of total iodothyronine turnover indicated that two-thirds of the Ts utilized per day by the iodine-sufficient rat arises from T4. If the Tr-Ts conversion ratio remains the same in iodine deficiency, then the analysis suggests that about 90% of the T3 arises directly from the thyroid. Therefore, it would appear that absolute Ts secretion by the thyroid increases severalfold during iodine deficiency. The fact that serum T3 remains constant and T4 decreases to extremely low levels, combined with previous observations that iodinedeficient animals appear to be euthyroid, is compatible with the hypothesis that T4 in the normal rat serves primarily as a precursor of T3. INTRODUCTIONThe thyroidal response to iodine deficiency has been an area of active investigation for many years. Previous studies in the rat reviewed by Studer and Greer indicate that when iodine intake is severely restricted there is an increase in thyroid weight, a decrease in protein-bound iodine (PBI)1 and an altered pattern of tracer iodine distribution in the thyroid gland (1). The last-mentioned changes include an increase in labeled monoiodotyrosine (MIT) and decrease in labeled diiodotyrosine (DIT) as well as a progressive increase in the ratio of labeled triiodothyronine (T3) to labeled thyroxine (T4). ...

“…Renewed interest in the problem was aroused by the demonstration by Braverman, Ingbar, and Sterling (22) that To to Ta conversion did in fact occur in man and that the earlier conclusion by Lassiter and Stanbury was premature. Additional evidence favoring the concept that Ts is the active hormone has been the finding of limited capacity anterior pituitary sites for T3 but not To (37) and the demonstration of stereospecific binding of T3 but not T4 by rat hepatic and renal nuclei (38).…”

Section: Discussionmentioning

confidence: 99%

Propylthiouracil inhibits the conversion of l-thyroxine to l-triiodothyronine

Oppenheimer¹,

Schwartz²,

Surks³

1972

Self Cite

266

A B S T R A C T 6-n-propylthiouracil (PTU) administered to male Sprague-Dawley rats maintained on 2 and 5 Ag L-thyroxine (T4)/100 g body weight resulted in a marked reduction in the rate of conversion of L-thyroxine to L-triiodothyronine (Ts). These effects could not be ascribed to induced hypothyroidism since the group maintained on 5 *g T4/day had normal levels of liver mitochondrial alpha glycerophosphate dehydrogenase. In confirmation of previous studies, PTU also reduced the fractional rate of deiodination of T&. These observations provide a possible explanation of the many published observations indicating that PTU antagonizes the tissue effects of T4 but not of T3. The data suggest that monodeiodination of To but not of T8 is essential before hormonal effects can be manifested at the cellular level.