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

Abstract

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

TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy

“…Indeed, some studies showed that hypothyroid patients treated with L-T 4 had impaired well-being despite their normal TSH levels (15,16). Meanwhile, patients with moderately suppressed TSH levels postoperatively had higher serum FT 4 levels and unchanged serum FT 3 levels compared with their native levels, findings that are in agreement with those of Silva & Larsen (13). Indeed, most physicians encounter patients on TSH-suppressive doses of L-T 4 therapy who have serum T 4 levels higher than the normal upper limit and normal T 3 levels (2,3,5).…”

“…However, serum TSH levels only reflect the feedback effect of thyroid hormones at the hypothalamic-pituitary level and, therefore, may not be an appropriate indicator of peripheral tissue euthyroidism (12). The TSH secretion from the pituitary is negatively regulated primarily by T 3 produced locally via the conversion of T 4 transported from the peripheral blood, which is keeping with the view that serum T 4 rather than T 3 has a dominant role in regulating TSH secretion (13). On the other hand, T 3 transported from the peripheral blood also has a role in regulating TSH secretion by the pituitary (14).…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Estimates suggest that at least half of the T 3 present in D2-expressing tissues is produced locally from deiodination of T 4 (86)(87)(88)(89). More recently D2 expression has been found in a large number of tissues and cells (90)(91)(92)(93)(94)(95)(96)(97)(98), illustrating the importance of defining its contribution to tissue-specific thyroid hormone signaling.…”

“…Studies have been standardized in rats but could in theory be applied in mice as well, provided that limitations due to body size and anesthesia are overcome. Tissues can be studied as a whole or fractionated to isolate the TR-containing nuclear fraction (66,(86)(87)(88)(89) 3 . Because the Tm(T 4 ) and Tm(T 3 ) are different, the administration of the two tracers should be timed so that both Tms coincide at the time animals are killed.…”

Thyroid-Stimulating Hormone Regulation and Transcription in Hypothyroidism

“…Approximately 50 to 60 % of T3 bound to TRs is locally produced by D2-mediated T4 to T3 conversion in the rat pituitary gland (Silva & Larsen, 1978). Human pituitary tissues also contain D2 (Itagaki et al, 1990).…”