Iodothyronine 5′-Deiodinase from Rat Kidney: Substrate Specificity and the 5′-Deiodination of Reverse Triiodothyr onine *

Leonard, Jack L.; Rosenberg, I. N.

doi:10.1210/endo-107-5-1376

Cited by 240 publications

(89 citation statements)

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“…When using T4 as substrate, 1 pM T3 was included in the reaction media, to prevent inner ring deiodination (5D). The lodide was separated by ion-exchange chromatography on Dowex-SOW-X2 columns equilibrated in 10% acetic acid (29). The protein content was determined using the method of Lowry et al (30).…”

Section: Methodsmentioning

confidence: 99%

Developmental Changes in Rat Brain 5′-Deiodinase and Thyroid Hormones during the Fetal Period: The Effects of Fetal Hypothyroidism and Maternal Thyroid Hormones

Oña¹,

Obregón²,

Rey³

et al. 1988

Pediatr Res

108

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ABSTRACT. We have studied the ontogenesis of 5'-deiodinase (5'D) activity in rat brain during fetal life, its capacity to respond to maternal or fetal hypothyroidism, and its regulation by maternal thyroid hormones. Type I1 5'D (5' D-11) activity increases 4-fold during the period studied (17 to 22 days of gestation), mainly between days 19 and 21. Fetal brain T4 concentrations increase in parallel with fetal plasma T4, whereas fetal brain T3 concentrations increase 18 times (days 17-21), six times more than would have been expected from the small increase in fetal plasma T3 levels. Maternal thyroidectomy did not affect 5'D-I1 activity or thyroid hormone concentrations in fetal brain (except brain T4 at 18 days of gestation). Fetal hypothyroidism, induced by giving a goitrogen (methimazole) to the mothers, depleted all fetal tissues studied, including the fetal thyroid, from thyroid hormones. By 19 days of gestation, the fetal brain was able to respond to hypothyroidism with a 3-to 5-fold increase in 5'D-I1 activity. Earlier onset of treatment with methimazole led to 2-to 3-fold increases in 5'D already at 17 and 18 days of gestation, showing that when fetal thyroid secretion starts the fetal brain 5'D-I1 is able to respond to hypothyroidism. Replacement of methimazole-treated mothers with physiological doses of T4, given by constant infusion, increased T4 and T3 concentrations in fetal brain, and inhibited fetal, as well as maternal, brain 5'D-I1 activity. But treatment of the mothers with T3 did not change T3 concentrations in the fetal brain, despite the increase in fetal plasma T3, and actually increased 5'D-I1 in fetal brain. Maternal cerebral 5'D-I1 was not inhibited by T3 treatment. Inverse relationships were found between the 5'D-I1 and thyroid hormone concentrations in the fetal brain. These correlations were not identical for fetuses from thyroidectomized and control mothers. In fetuses from thyroidectomized dams, brain 5'D-I1 is more sensitive to a decrease in brain T4 than in the progeny of control

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Section: Methodsmentioning

confidence: 99%

Developmental Changes in Rat Brain 5′-Deiodinase and Thyroid Hormones during the Fetal Period: The Effects of Fetal Hypothyroidism and Maternal Thyroid Hormones

Oña¹,

Obregón²,

Rey³

et al. 1988

Pediatr Res

108

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“…-from 3,3 ,5 -[ 125 I]-triiodothyronine (rT 3 , DuPont, Bad Homburg, Germany) in the absence or presesence of 1 mM PTU (6-n-propyl-2-thio-uracil) using 10 nM non-radioactive rT 3 for pituitary and cell-culture homogenates and 10 µM for liver homogenates (Leonard & Rosenberg 1980). The fraction of iodide release blocked by 1 mM PTU was assigned to D1, the residual activity not inhibited by PTU was ascribed to D2.…”

Section: Biochemical Assaysmentioning

confidence: 99%

Effects of proinflammatory cytokines on anterior pituitary 5'-deiodinase type I and type II

Baur¹,

Bauer²,

Jarry³

et al. 2000

Journal of Endocrinology

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Cytokines are locally produced in the anterior pituitary and act through para-/autocrine mechanisms to modulate cell growth and hormone production. 5 -Deiodinases type I (D1) and type II (D2) are also expressed in the anterior pituitary and play an integrative role in the regulation of hormone production and pituitary feedback. D1 activity is known to be regulated by proinflammatory cytokines in liver and thyroid. Therefore, we examined the effects of IL-1 , IL-6 and TNF on 5 -deiodinase activities in reaggregates of rat anterior pituitaries and rat somatomammotroph GH3 cells cultured alone, or in a bicameral culture system together with the murine folliculo-stellate (FS) cell line TtT/Gf. In reaggregate cultures of rat anterior pituitaries IL-1 stimulated D1 and D2 dosedependently and D2 activity was increased by TNF . When GH3 cells were cocultured with TtT/Gf cells, D2 activities were 2·3-fold lower than in GH3 cells cultured alone. TNF (50 ng/ml) and IL-6 (100 U/ml) stimulated D2 in GH3 cells when the cells were cultured alone and treated with these cytokines for 24 h. When TtT/Gf cells in the coculture model were treated with IL-1 , TNF and IL-6, no effect on D1 or D2 activities in GH3 cells was observed.In male, adult rats a single LPS injection (i.p.) stimulated D2 and D1 activities in the anterior pituitary, and decreased liver D1 activities and serum TSH levels. In vitro, LPS stimulation of the coculture model of GH3 and FS cells also increased D1 activity.Electrophoretic mobility shift assays (EMSAs) revealed that IL-1 and TNF activate the transcription factor NF B in reaggregates of rat anterior pituitaries and in TtT/Gf cells cultured alone or cocultured with GH3 cells. Taken together, these findings imply that in anterior pituitary cells 5 -deiodinase activities are stimulated by locally produced cytokines in a para-/autocrine manner but cell types other than FS cells seem to mediate some of the effects.

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“…Pituitary T4 5'-deiodinase activity in homogenates and tissue fragments is increased in hypothyroidism and decreased in hyperthyroidism (11,12), whereas opposite changes are observed slices, homogenates, and microsomes from liver and kidney, as reviewed recently (7). 3,3',5'-Triiodothyronine (reverse T3, rT3) is a more suitable substrate than T4 for the 5'-deiodinase activities of liver and kidney, judging from the higher ratio of Vmax to Kni for rT3 (25,26). We have recently deAbbreviations used in this paper: DTT, dithiothreitol; G1l, growth hormone; PTU, 6-n-propvl-2-thiouracil; rT3, .3,3',5'-triiodothyronine; tetrac, tetraiodothyroacetic acid; tetra prop, tetraiodothyropropionic acid; T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin; triac, 3,3',5-triiodothyroacetic acid; 3,3'-T2, 3,3'-diiodothyronine; V,,l,, maximum velocity.…”

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.

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195

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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

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Iodothyronine 5′-Deiodinase from Rat Kidney: Substrate Specificity and the 5′-Deiodination of Reverse Triiodothyr onine *

Cited by 240 publications

References 0 publications

Developmental Changes in Rat Brain 5′-Deiodinase and Thyroid Hormones during the Fetal Period: The Effects of Fetal Hypothyroidism and Maternal Thyroid Hormones

Developmental Changes in Rat Brain 5′-Deiodinase and Thyroid Hormones during the Fetal Period: The Effects of Fetal Hypothyroidism and Maternal Thyroid Hormones

Effects of proinflammatory cytokines on anterior pituitary 5'-deiodinase type I and type II

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

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