In Vitro Studies on Thyroid Hormone Receptors

Samuels, Herbert H.

doi:10.1016/b978-0-12-526303-0.50008-4

Cited by 32 publications

(15 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…T 3 accounts for most of the biological activity of thyroid hormones, and most well-characterized cellular responses to T 3 have been demonstrated to be mediated through specific binding of T 3 to its nuclear receptor, a nonhistone chromatin protein (56,57). For these reasons, studies were undertaken in our laboratory to investigate the effects of DPH on specific nuclear binding of T 3 in rat liver and anterior pituitary, two tissues which are both thyroid hormone responsive and which contain high concentrations of nuclear T 3 receptors.…”

Section: Influence Of Dph On Cellular Actions Of Tmentioning

confidence: 99%

See 1 more Smart Citation

Multiple Effects of 5,5′-Diphenylhydantoin on the Thyroid Hormone System*

Smith

Surks

1984

Endocrine Reviews

View full text Add to dashboard Cite

The studies described above indicate the likelihood of a significant effect of DPH on cellular functions that are regulated by T3 at concentrations of DPH that occur during treatment of patients with Dilantin. Thus, it is possible that sensitive measures of cellular thyroid status in man, if available, might indicate that DPH treatment causes a mild hypothyroid state which may be partially compensated for by an activity of DPH as a partial thyroid hormone agonist. This review illustrates the complex array of interactions of DPH with multiple elements of the thyroid hormone system ranging from effects on T4 and T3 metabolism, serum protein binding, serum and cellular concentration of thyroid hormones, nuclear T3 binding and biologic actions of T3, to effects on hypothalamic and pituitary regulation of TSH. At the present time, no single biological mechanism common to these manifold interactions is apparent. Moreover, many of these interactions are not yet completely understood despite clinical and basic biological investigation for over 20 years. Continued investigation would appear fruitful especially for further understanding of hypothalamic regulation of TSH secretion, of cellular uptake of T3, and of the use of DPH as a partial thyroid hormone agonist. Finally, since DPH attenuates the effect of T3 at the level of the nuclear T3 receptor, the drug may serve as a prototype of agents that may be useful in the management of thyrotoxicosis.

show abstract

Section: Influence Of Dph On Cellular Actions Of Tmentioning

confidence: 99%

“…Studies of analogs of T 4 and T 3 have generally shown that binding affinity for the nuclear receptor correlates with biological activity (56,57). To date, no analog that has a high affinity for the nuclear receptor has been found to be a thyroid hormone antagonist.…”

Section: Influence Of Dph On Cellular Actions Of Tmentioning

confidence: 99%

Multiple Effects of 5,5′-Diphenylhydantoin on the Thyroid Hormone System*

Smith

Surks

1984

Endocrine Reviews

View full text Add to dashboard Cite

show abstract

“…In the rat, thyroidectomy markedly lowers the pituitary and serum growth hormone content, and this is rapidly restored by thyroid hormone administration (9)(10)(11)(12). The onset and timecourse of growth hormone accumulation in GH, cells (36) and in the rat pituitary in vivo (12) are essentially identical, which suggests that thyroid hormone induces this response by the same mechanism in GH, cells and the pituitary somatotroph. It has been reported (13) that thyroid hormone does not induce an increase in growth hormone production in dispersed anterior pituitary cells.…”

Section: Introductionmentioning

confidence: 96%

“…2) to estimate total nuclear receptor levels using iodothyronines other then L-T3, i.e., triac, D-T3, and L-T4, if the affinity of these compounds relative to L-T3 is determined. 36-h incubation ofL-1251-T4 wvith GH1 cells. L-125I-T4, purified as previously described (1,32), was incubated with GH1 cells at 50 nM with and without a 500-foldl molar excess of nonradioactive L-T4.…”

Section: Introductionmentioning

confidence: 99%

Relationship of receptor affinity to the modulation of thyroid hormone nuclear receptor levels and growth hormone synthesis by L-triiodothyronine and iodothyronine analogues in cultured GH1 cells.

Samuels¹,

Stanley²,

Casanova³

1979

J. Clin. Invest.

122

View full text Add to dashboard Cite

A B S T R A C T We have previously demonstrated that L-triiodothyronine (L-T3) induces an increase in growth hormone synthesis and messenger RNA in cultured GH1 cells, a rat pituitary cell line. In addition to regulating the growth hormone response, L-T3 elicits a time-and dose-dependent reduction in the level of its nuclear receptor, which is a direct function of the occupancy of the receptor binding site. In this study we have compared the relative affinity of L-T3, triiodothyroacetic acid, D-triiodothyronine (D-T3), and L-thyroxine (L-T4) for the receptor with the induction ofthe growth hormone synthesis and the ability of these compounds to elicit a reduction in thyroid hormone nuclear receptor levels. Triiodothyroacetic acid and D-T3 were specifically examined because the biologic effect of these compounds in the intact rat is significantly lower than predicted by their affinity for the receptor using isolated rat liver nuclei in vitro. In intact cells each compound demonstrated an excellent relationship between the relative receptor affinity, the induction of growth hormone production, and the concentration-dependent reduction in nuclear receptor levels. With the exception of D-T3, the relative affinity of iodothyronine was identical for the receptor using intact cells in serum-free media, or isolated GH, cell nuclei in vitro. The apparent receptor affinity of D-T3 with intact cells was 5.5-fold lower than with isolated nuclei, which suggests a decrease in cell entry of D-T3 relative

show abstract

“…In GH3 cells, derived from rat pituitary tumor tissue, thyroid hormone modulates the rate of synthesis of at least six proteins, including GH (2). Ample evidence has been presented that these actions are initiated by the binding of 3,3',5-triiodothyronine (T3) to a nuclear chromatin-associated receptor (3)(4)(5)(6)). Yet, on some occasions a better correlation of serum TSH with serum thyroxine (T4) than with serum T3 concentrations is observed (7).…”

Section: Introductionmentioning

confidence: 99%

Evidence for Two Pathways of Iodothyronine 5′-Deiodination in Rat Pituitary That Differ in Kinetics, Propylthiouracil Sensitivity, and Response to Hypothyroidism

Tj¹,

Kaplan²,

Leonard³

et al. 1983

J. Clin. Invest.

195

View full text Add to dashboard Cite

A B S T R A C T We have studied 5'-deiodination of thyroxine (T4) and 3,3',5'-triiodothyronine (rT3) in rat pituitary tissue in vitro, with respect to substrate specificity, reaction kinetics, effects of 6-n-propyl-2-thiouracil (PTU), and the time course of effects of thyroid hormone depletion and repletion. Removal of one phenolic iodine or both tyrosyl iodines from the T4 molecule resulted in compounds that were not deiodinated, but alterations in the alanine side chain had little effect.5'-Deiodination of 2 nM rT3 by pituitary microsomes from euthyroid rats was inhibited >90% by 1 mM PTU, but was inhibited <10% by 100 nM T4. The apparent Michaelis constant (K.n) and maximum velocity (Vll~ax) for rT3 at 20 mM dithiothreitol (DTT) were 33 nM and 84 pmol/mg protein per h. This reaction followed ping-pong type reaction kinetics when concentrations of DTT sitive rT3 5'-deiodination (K, = 1.3 nM). T4 5'-deiodination by hypothyroid microsomes was not affected by PTU, was competitively inhibited by rT3 (Ki, 1.7 nM), and exhibited sequential type reaction kinetics with DTT as cosubstrate. When T4 5'-deiodination was measured in euthyroid and hypothyroid microsomes, respectively, the apparent Km and Vma. for T4 at 20 mM DTT, were 0.9 nM and 0.55 pmol/mg protein per h (euthyroid), and 0.8 nM and 6.9 pmol/mg protein per h (hypothyroid).The T4 5'-deiodination rate and the PTU-insensitive, but not total, rT3 5'-deiodination rate (i.e. measured in the presence and the absence of 1 mM PTU, respectively) in pituitary homogenates were significantly elevated 24 h after thyroidectomy. PTU-insensitive activity continued to increase until at .30 d after thyroidectomy it was 11 times the PTU-insensitive activity in controls. At the latter time, PTU-sensitive rT3 5'-deiodinase activity appeared to be decreased. The increase in PTU-insensitive T4 and rT3 5'-deiodination observed 48

show abstract

In Vitro Studies on Thyroid Hormone Receptors

Cited by 32 publications

References 62 publications

Multiple Effects of 5,5′-Diphenylhydantoin on the Thyroid Hormone System*

Multiple Effects of 5,5′-Diphenylhydantoin on the Thyroid Hormone System*

Relationship of receptor affinity to the modulation of thyroid hormone nuclear receptor levels and growth hormone synthesis by L-triiodothyronine and iodothyronine analogues in cultured GH1 cells.

Evidence for Two Pathways of Iodothyronine 5′-Deiodination in Rat Pituitary That Differ in Kinetics, Propylthiouracil Sensitivity, and Response to Hypothyroidism

Contact Info

Product

Resources

About