Inhibition of intrathyroidal dehalogenation by iodide

in Journal of Endocrinology
Authors:
Juan C Solis-S
Search for other papers by Juan C Solis-S in
Current site
Google Scholar
PubMed
Close
,
Patricia Villalobos Department of Biomedical Research, Department of Cellular and Molecular Neurobiology, Department of Physiology and Pharmacology, School of Medicine, Autonomous University of Queretaro, Clavel 200, Queretaro, Queretaro 76017, Mexico

Search for other papers by Patricia Villalobos in
Current site
Google Scholar
PubMed
Close
,
Aurea Orozco Department of Biomedical Research, Department of Cellular and Molecular Neurobiology, Department of Physiology and Pharmacology, School of Medicine, Autonomous University of Queretaro, Clavel 200, Queretaro, Queretaro 76017, Mexico

Search for other papers by Aurea Orozco in
Current site
Google Scholar
PubMed
Close
,
Guadalupe Delgado Department of Biomedical Research, Department of Cellular and Molecular Neurobiology, Department of Physiology and Pharmacology, School of Medicine, Autonomous University of Queretaro, Clavel 200, Queretaro, Queretaro 76017, Mexico

Search for other papers by Guadalupe Delgado in
Current site
Google Scholar
PubMed
Close
,
Andres Quintanar-Stephano Department of Biomedical Research, Department of Cellular and Molecular Neurobiology, Department of Physiology and Pharmacology, School of Medicine, Autonomous University of Queretaro, Clavel 200, Queretaro, Queretaro 76017, Mexico

Search for other papers by Andres Quintanar-Stephano in
Current site
Google Scholar
PubMed
Close
,
Pablo Garcia-Solis
Search for other papers by Pablo Garcia-Solis in
Current site
Google Scholar
PubMed
Close
,
Hebert L Hernandez-Montiel
Search for other papers by Hebert L Hernandez-Montiel in
Current site
Google Scholar
PubMed
Close
,
Ludivina Robles-Osorio
Search for other papers by Ludivina Robles-Osorio in
Current site
Google Scholar
PubMed
Close
, and
Carlos Valverde-R Department of Biomedical Research, Department of Cellular and Molecular Neurobiology, Department of Physiology and Pharmacology, School of Medicine, Autonomous University of Queretaro, Clavel 200, Queretaro, Queretaro 76017, Mexico

Search for other papers by Carlos Valverde-R in
Current site
Google Scholar
PubMed
Close

Free access

Sign up for journal news

Iodide is a trace element and a key component of thyroid hormones (TH). The availability of this halogen is the rate-limiting step for TH synthesis; therefore, thyroidal iodide uptake and recycling during TH synthesis are of major importance in maintaining an adequate supply. In the rat, the thyroid gland co-expresses a distinctive pair of intrathyroidal deiodinating enzymes: the thyroid iodotyrosine dehalogenase (tDh) and the iodothyronine deiodinase type 1 (ID1). In the present work, we studied the activity of these two dehalogenases in conditions of hypo- and hyperthyroidism as well as during acute and chronic iodide administration in both intact and hypophysectomized (HPX) rats. In order to confirm our observations, we also measured the mRNA levels for both dehalogenases and for the sodium/iodide symporter, the protein responsible for thyroidal iodide uptake. Our results show that triiodothyronine differentially regulates tDh and ID1 enzymatic activities, and that both acute and chronic iodide administration significantly decreases rat tDh and ID1 activities and mRNA levels. Conversely, both enzymatic activities increase when intrathyroidal iodide is pharmacologically depleted in TSH-replaced HPX rats. These results show a regulatory effect by iodide on the intrathyroidal dehalogenating enzymes and suggest that they contribute to the iodide-induced autoregulatory processes involved in the Wolff–Chaikoff effect.

Abstract

Iodide is a trace element and a key component of thyroid hormones (TH). The availability of this halogen is the rate-limiting step for TH synthesis; therefore, thyroidal iodide uptake and recycling during TH synthesis are of major importance in maintaining an adequate supply. In the rat, the thyroid gland co-expresses a distinctive pair of intrathyroidal deiodinating enzymes: the thyroid iodotyrosine dehalogenase (tDh) and the iodothyronine deiodinase type 1 (ID1). In the present work, we studied the activity of these two dehalogenases in conditions of hypo- and hyperthyroidism as well as during acute and chronic iodide administration in both intact and hypophysectomized (HPX) rats. In order to confirm our observations, we also measured the mRNA levels for both dehalogenases and for the sodium/iodide symporter, the protein responsible for thyroidal iodide uptake. Our results show that triiodothyronine differentially regulates tDh and ID1 enzymatic activities, and that both acute and chronic iodide administration significantly decreases rat tDh and ID1 activities and mRNA levels. Conversely, both enzymatic activities increase when intrathyroidal iodide is pharmacologically depleted in TSH-replaced HPX rats. These results show a regulatory effect by iodide on the intrathyroidal dehalogenating enzymes and suggest that they contribute to the iodide-induced autoregulatory processes involved in the Wolff–Chaikoff effect.

Introduction

Iodide is a micronutrient and a key component of thyroid hormones (TH). Its availability is rate limiting for TH synthesis, and its scarcity in the biosphere can lead to insufficient intake and continues to be a worldwide public health concern (Zimmermann 2009). At the level of the thyroid, the limited availability of iodide is countered by several mechanisms. Uptake of iodide against an electrochemical gradient is exerted by the sodium/iodide symporter (NIS; Dai et al. 1996, Kopp & Solis-S 2009). Moreover, a pair of thyroidal dehalogenases recycles iodide in the rat thyroid gland: iodotyrosine dehalogenase (tDh) and iodothyronine deiodinase type 1 (ID1). tDh (human homolog iodotyrosine deiodinase, IYD or DEHAL1) deiodinates mono- and diiodotyrosines (DIT), thereby recycling iodide for TH synthesis (Gnidehou et al. 2004, Solis-S et al. 2004). ID1 (human homolog DIO1) belongs to the family of selenodeiodinases, which also includes the type 2 (ID2) and type 3 (ID3) isoenzymes. ID1 is able to deiodinate iodothyronines both at the 5′ and 5 positions, while ID2 and ID3 only remove iodide from the 5′ and 5 positions respectively. In addition, a physiological role for ID1 as a scavenger enzyme has been recently proposed due to its capacity to remove iodide from reverse triiodothyronine (rT3) and other inactive and sulfated iodothyronines (St Germain et al. 2009). tDh and the three iodothyronine selenodeiodinases are the only enzymes known to catalyze reductive dehalogenation in mammals, though they are structurally and mechanistically different (Rokita et al. 2010). However, and in spite of the importance of dehalogenation, little is known about the regulation of this intrathyroidal enzymatic system. Early studies in intact rats reported that TSH administration increases rat tDh (rtDh) activity (Roche et al. 1953, Maayan & Rosenberg 1963). Similarly, thyroidal ID1 activity (Erickson et al. 1982) and mRNA (Toyoda et al. 1992) are increased by TSH and TH in vivo and in vitro. Remarkably, iodide itself acts as a regulator of TH synthesis. Evidence supporting this came as early as 1923 in a pioneer study highlighting the inhibitory effect of iodide in patients with Graves' disease (Plummer 1923). Further in vitro (Morton et al. 1944) and in vivo (Wolff & Chaikoff 1948) studies showed that thyroidal iodide organification was blocked by the administration of large quantities of inorganic iodide. This inhibition, or arrest in hormonogenesis, which is secondary to elevated plasmatic iodide levels, is known as the Wolff–Chaikoff effect (Wolff & Chaikoff 1948). However, this blockade is transitory, and iodide organification generally resumes once the serum iodide concentration decreases below a threshold level. Furthermore, even when the circulating levels of iodide remain elevated, the thyroid gland resumes iodide organification after 24–48 h, a situation known as ‘the escape’ or ‘adaptation’ to the Wolff–Chaikoff effect (Wolff & Chaikoff 1948). It is known that this escape phenomenon involves, among other mechanisms, a reduced expression of NIS, thus decreasing iodide uptake and total intrathyroidal iodide content (Uyttersprot et al. 1997, Eng et al. 1999). Although it was described more than 60 years ago, several important questions remain to be answered about this noteworthy thyroidal autoregulatory mechanism.

In the present work, we studied the activity and mRNA expression of the intrathyroidal dehalogenating enzymes rtDh and ID1, during hypo- and hyperthyroidism, as well as during acute and chronic iodide administration, in both intact and hypophysectomized (HPX) rats, in order to determine how they are regulated in various physiological conditions.

Materials and Methods

Reagents

Bovine TSH (bTSH), T3, methimazole (MMI), KClO4, iodide, DIT, flavin adenine dinucleotide (FAD), reduced NADPH, and rT3 were purchased from Sigma Chemical Co.; NaI125 (specific activity: 17.4 Ci/mg) was purchased from Amersham Pharmacia. 125I-labeled rT3 (specific activity: 1174 μCi/μg) was obtained from Perkin Elmer-NEN, Inc. (Boston, MA, USA). Resins AG 50W-X8 and AG 50W-X2 (both mesh size 100–200) were acquired from Bio-Rad Laboratories. Dithiothreitol (DTT) was obtained from Calbiochem (La Jolla, CA, USA). Radiolabeled substrates were purified prior to use by means of a SEP-PACK C18 cartridge from Millipore Waters Chromatography (Boston, MA, USA).

Animals, HPX, and housing

Adult male rats (∼300 g body weight) of the Sprague–Dawley strain were maintained six per cage in a controlled environment (22 °C, 12 h light:12 h darkness cycle) and fed with standard Purina chow and water made available ad libitum. HPX were performed via ventral neck as described previously (Alvarez-Buylla et al. 1991). The animals were maintained in a separate, controlled environment (30 °C, 12 h light:12 h darkness cycle) and fed with red apples and 2% glucose in drinking water for 7 days post surgery. All treatments were initiated 1 week after surgery. Procedures regarding handling and killing of animals were reviewed and approved by the Animal Welfare Committee of the Institute of Neurobiology.

Experimental protocols

To dissect the putative in vivo effects of TSH, T3, and iodide upon the activity of the two thyroidal enzymes (rtDh and ID1), groups of 7–15 intact or HPX rats were handled according to the experimental protocols detailed in Table 1. Intact animals were divided into the following five groups: control, hypothyroid (treated with MMI+KClO4 and I-depleted), hyperthyroid (T3-treated), acute iodide load (24 h), and chronic iodide load (7 days). HPX rats were divided into the following five groups: HPX control, HPX+TSH, HPX+TSH+I-depleted, HPX+T3, and HPX+TSH+T3.

Table 1

Treatments received by the experimental groups and their expected thyroidal state

GroupsExperimental protocolnTreatmentExpected thyroidal state
Intact pituitaryControl15No treatmentControl
Hypothyroid (I-depleted)150.1% MMI+1% KClO4 in DW ad libitum for 7 daysDisruption of TH-negative feedback on HPT axis: increased TSH and low TH. Iodide-depleted thyroid gland
Hyperthyroid15Single dose (100 μg/100 g BW) of T3 via i.p. 24 h before killingInhibition of HPT axis by TH: low TSH and high TH levels
Acute KI load150.05% KI in DW for 24 hHPT axis undisrupted, at 24 h: thyroid with acute WCE; at 7 days: thyroid adapted to WCE
Chronic KI load150.05% KI in DW for 7 days
HypophysectomizedControl7Vehicle via i.p. every 12 h for 3 daysEndogenous TSH absent: hypothyroidism due to impaired TH production
TSH-replaced71 IU bTSH i.p. every 12 h for 3 daysTH synthesis stimulated by TSH replacement; controlled TSH levels
TSH+I-depleted70.1% MMI+1% KClO4 in DW for 7 days ad libitum +1 IU bTSH i.p. every 12 h for 3 daysIodide-depleted thyroid gland, controlled TSH levels without TH production
T3-replaced8Single dose (100 μg/100 g BW) of T3 via i.p. 24 h before killingHigh TH levels with suppressed TSH
TSH+T3-replaced8Single dose (100 μg/100 g BW) of T3 via i.p. 24 h before killing +1 IU bTSH i.p. every 12 h for 3 daysHigh TH levels with controlled TSH replacement

MMI, methimazole; KClO4, potassium perchlorate; DW, drinking water; KI, potassium iodide; BW, body weight; HPT axis, hypothalamic–pituitary–thyroidal axis; WCE, Wolff–Chaikoff effect.

Hormone measurement, sample preparation, and deiodination assay

Animals were killed by decapitation, and blood was collected for TSH and T3 measurements. For T3, a single-species-adapted antibody technique was used as previously described (Anguiano et al. 1991). In the case of TSH, a rat TSH (rTSH-125I) Biotrak Assay System (Amersham Biosciences) was used as indicated by the manufacturer. The enzymatic assays for rtDh and ID1 activities were performed as previously described (Solis-S et al. 2004). In brief, thyroid, liver, and kidney tissue samples were homogenized (1:5 w/v) in phosphate (0.5 M, pH 7.4) and HEPES buffer (0.01 M, pH 7.0) for rtDh and ID1 respectively. Homogenates were centrifuged at 13 000 g for 5 min, 4 °C, divided in aliquots, and protein content was measured by Bradford's method (Bradford 1976). For the rtDh assay, 125I-DIT was radiolabeled by the exchange method (Cahnman 1972) to a mean-specific activity of 765±110 μCi/μmol; the assay mixture contained 2 μM DIT, 8 pmol 125I-DIT (∼10 000 c.p.m.), 200 μg protein, 50 mM 2-mercaptoethanol, 200 mM KCl, 30 μM FAD, 1.5 mM MMI, and 30 μM NADPH in a final volume of 500 μl. The ID1 assay mixture contained 1 μM rT3, 200 fmol 125I-rT3 (∼50 000 c.p.m.), 20 μg protein, and 5 mM DTT in a final volume of 100 μl. Both assay mixtures were incubated in a covered water bath with shaking for 60 min at 37 °C, and the reactions were stopped by adding 50% human plasma, 10 mM propylthiouracil, and 10% trichloroacetic acid. In both cases, the assay mixture was centrifuged (1300 g for 15 min), and the supernatant was decanted onto a 1 ml AG 50W-X2 column equilibrated in 10% acetic acid and eluted with 2 ml of 10% acetic acid. In all cases, <30% of the substrate was consumed during the reaction. The amount of 125I in the eluate, which is an index of enzyme deiodinating activity, was determined in a gamma scintillation counter. Results for both enzymes are expressed as picomoles of 125I-released/mg protein×h. All enzymatic assays were performed in duplicate, with a minimum of three repetitions.

Quantitative real-time PCR

mRNA extraction, reverse transcription, and real-time PCR were performed as previously described (Anguiano et al. 2007). Briefly, 2 μg total RNA extracted from thyroid tissue (TRIZOL reagent; Life Technologies) was reverse-transcribed (Superscript II system; Invitrogen) according to the manufacturer's instructions. PCR was performed on the sequence detector system Roto-Gene 3000 (Corbett Research, Mortlake, NSW, Australia) using SYBR green as a marker for DNA amplification. Gene-specific primers are listed in Table 2. The reaction was performed with 1 μl cDNA template and the quantitative real-time PCR (qPCR) supermix-UDG kit (Invitrogen), using 40 cycles of three-step amplification (94 °C for 30 s, 58 °C for 30 s, and 72 °C for 30 s). The PCR generated only the expected, specific amplicon, which was corroborated in each case by the melting temperature profile (dissociation curve) and by electrophoresis of 5 μl of the PCR product through a 2% agarose gel containing ethidium bromide in TAE (0.04 M Tris-acetate/0.01 M EDTA electrophoresis buffer). No PCR products were observed in the absence of template. Gene expression was calculated using the Dcycle threshold (DCt) method and normalized to actin mRNA content. All measurements were performed in triplicate.

Table 2

Oligonucleotide sequences employed for real-time PCR

GenesSense sequenceAntisense sequenceAlignment temperature (°C)
ActinACA GAG TAC TTG CGC TCA GGACCA TCA TGA AGT GTG ACG TTG58
rtDhGAC CAT TCT CCT CAC TCGGC AGA CTCT CCT ATG AGA AT58
ID1ATT TGA CCA GTT CAA GAG ACT CGT AGCCA CGT TGT TCT TAA AAG CCC A58
NISCCG GAT CAA CCT GAT GGA CTCCT GAG GGT GCC ACT GTA AG58

rtDh, rat thyroidal dehalogenase; ID1, iodothyronine deiodinase type 1; NIS, sodium/iodide symporter.

Statistical analysis

Statistical analyses were performed with the Prism software (v. 4.03, GraphPad Software, Inc., San Diego, CA, USA). Comparison between groups was performed by one-way ANOVA followed by Tukey's multiple comparison/post hoc tests wherever applicable; a P value ≤0.05 was considered statistically significant. Results are shown as the mean±s.e.m.

Results

TSH and T3 serum levels

Table 3 summarizes circulating levels of TSH and T3 in all experimental groups. As expected, TSH levels increased significantly in the hypothyroid group and decreased in the hyperthyroid group, while T3 exhibited the opposite pattern. Iodide administration had no significant effect on either hormone. Pituitary ablation resulted in TSH and T3 levels well below control values. Owing to the lack of cross reactivity between the administered bTSH with the endogenous rat hormone with the RIA kit employed, TSH replacement was not reflected on circulating levels (Table 3). However, TSH replacement significantly stimulated T3 secretion by the intact thyroid gland. Conversely, this response to TSH replacement in the thyroid gland of HPX rats, which were I-depleted, was blunted. As expected, T3 levels in HPX rats, either T3- or TSH+T3-replaced, were significantly increased.

Table 3

TSH and triiodothyronine (T3) serum values

GroupExperimental protocolSerum TSH (ng/ml)Serum T3 (ng/dl)
IntactControl5.69±0.670.29±2.9
Hypothyroid (I-depleted)11.61±0.922.5±3.3*
Hyperthyroid1.82±0.2*254.6±37.2
Acute KI load5.47±0.948±2.9
Chronic KI load4.75±1.761.64±5.5
HPXControlNot detected12.22±0.7*
TSH-replacedNot detected125.3±26.5*
TSH+I-depletedNot detected40.5±0.8
T3-replacedNot detected245.3±27.9
TSH+T3-replacedNot detected240.7±23.9

*P<0.05, compared to the control group; P<0.001, compared to the control group.

Effect of hypo- and hyperthyroidism on rtDh and ID1 enzymatic activities

Intact rats rendered hypothyroid by the MMI+KClO4 treatment (the I-depleted group) showed a 200 and 50% increase in rtDh and ID1 activities respectively (Fig. 1). However, administration of T3 differentially regulated the activity of the two enzymes: rtDh decreased by 50%, whereas ID1 increased by 75% (Fig. 1).

Figure 1
Figure 1

Effect of hypo and hyperthyroidism on rtDh and ID1 activities in the thyroid gland of intact rats. Each bar shows the mean±s.e.m. of three independent enzymatic assays, each performed in duplicate. Asterisks indicate significant differences as compared to control animals (*P<0.05, **P<0.001). Further details are in the text.

Citation: Journal of Endocrinology 208, 1; 10.1677/JOE-10-0300

Effect of acute and chronic iodide administration on rtDh and ID1 dehalogenating activities

As depicted in Fig. 2, rtDh and ID1 activities were significantly decreased in intact rats after exposure to either an acute (24 h) or a chronic (7 days) iodide overload. This inhibitory effect of the halogen was sustained up to day 7 of treatment, showing a 60 and 50% decrease for rtDh and ID1 respectively (Fig. 2).

Figure 2
Figure 2

Effect of acute (24 h) and chronic (7 days) KI load on rtDh and ID1 activities in the thyroid gland of intact rats. Each bar shows the mean±s.e.m. of three independent enzymatic assays performed in duplicate. Asterisks indicate significant differences as compared to control animals (**P<0.001). Further details are in the text.

Citation: Journal of Endocrinology 208, 1; 10.1677/JOE-10-0300

Effect of HPX and iodide depletion on both enzymatic activities

To further dissect the effects of TSH and T3, HPX animals were exposed to several experimental manipulations. Thus, TSH replacement increased rtDh and ID1 activities by 2.8- and 9-fold respectively (Fig. 3). This stimulatory effect of TSH on rtDh and ID1 activities was dramatically enhanced (to 6- and 52-fold increases respectively) when intrathyroidal iodide was depleted by concomitant MMI+KClO4 treatment (Fig. 3). As in the case of hyperthyroid intact animals, in T3-replaced HPX rats, only ID1 activity exhibited a significant increase (17-fold, Fig. 3). Furthermore, when T3 was combined with TSH, the activity of both enzymes significantly increased relative to control animals. However, when comparing this group to the HPX+T3-treated animals, the increase was only significant for rtDh (Fig. 3).

Figure 3
Figure 3

Effect of TSH, MMI/KClO4, and T3 treatments on rtDh and ID1 activities in thyroid glands of HPX rats. Each bar shows the mean±s.e.m. of three independent enzymatic assays performed in duplicate. Different letters indicate significant differences (P<0.05) between the groups. Further details are in the text.

Citation: Journal of Endocrinology 208, 1; 10.1677/JOE-10-0300

Effect of hypo- and hyperthyroidism on ID1 activity in liver and kidney of HPX rats

ID1 activity in kidney and liver was significantly up-regulated by TSH in HPX rats, increasing 100 and 150% respectively (Fig. 4). However, this TSH stimulatory effect was not observed in I-depleted rats in which endogenous T3 synthesis was blocked by MMI+KClO4 (Fig. 4). Nevertheless, T3 alone was sufficient to increase ID1 activity in both tissues by 320 and 400% in liver and kidney respectively (Fig. 4). When T3 and TSH were co-administered, kidney and liver ID1 activity increased 130 and 320% respectively (Fig. 4).

Figure 4
Figure 4

Effect of TSH, MMI/KClO4, and T3 treatments on ID1 activity in liver and kidney of HPX rats. Each bar shows the mean±s.e.m. of three independent enzymatic assays performed in duplicate. Comparison between groups was performed by one-way ANOVA followed by Tukey's post hoc tests. Different letters indicate significant differences (P<0.05) between the groups. Further details are in the text.

Citation: Journal of Endocrinology 208, 1; 10.1677/JOE-10-0300

Effect of iodide on tDh and ID1 mRNA expression

The expression levels of mRNA for tDh and ID1 in the thyroid of the hypothyroid, hyperthyroid, and the acute and chronic iodide-treated groups were determined. mRNA levels for the HPX group were not measured due to the limited volume of tissue available. Both tDh and ID1 mRNA expression diminished during acute iodide administration. However, only tDh mRNA remained significantly decreased during chronic iodide administration (Fig. 5). In addition, NIS mRNA levels were increased in hypothyroidism, and profoundly decreased in the hyperthyroid state, as well as during acute and chronic iodide administration (Fig. 5).

Figure 5
Figure 5

Effect of hypothyroidism, hyperthyroidism, and acute and chronic iodide load on thyroidal mRNA levels of tDH, ID1, and NIS. Results are presented as normalized mRNA levels relative to those of the corresponding control. Actin served as an internal control and was used to normalize for differences in input RNA. Groups not shown (tDH and ID1 for both hyperthyroidism and hypothyroidism) did not differ significantly from their respective controls. Data are expressed as mean±s.e.m. of three independent measurements. Asterisks indicate significant difference from the corresponding controls (**P<0.001).

Citation: Journal of Endocrinology 208, 1; 10.1677/JOE-10-0300

The results obtained for both enzymes with the different experimental protocols are summarized in Table 4.

Table 4

Summary of results. Statistically significant increments/decrements are shown by comparing each experimental group to their corresponding control (see figures)

Experimental protocolrtDhtID1NIS
ActivitymRNAActivitymRNAmRNA
Intact rats
 Hypothyroid (I-depleted)
 Hyperthyroid
 Acute KI load
 Chronic KI load
rtDhtID1hID1kID1
Hypophysectomized rats (activity)
 TSH-replaced
 TSH+I-depleted
 T3-replaced
 TSH+T3-replaced

↑, increase; ↓, decrease; ↔, no change; ND, not determined; tID1, thyroidal ID1; hID1, hepatic ID1; kID1, kidney ID1.

Discussion

To the best of our knowledge, this is the first study to examine the regulation of the intrathyroidal dehalogenases rtDh and ID1 simultaneously. Early reports have shown the important regulatory effect of TSH on rtDh, as well as of both TSH and TH on ID1 (Roche et al. 1953, Maayan & Rosenberg 1963, Erickson et al. 1982, Toyoda et al. 1992). By dissecting in vivo the influence of the three major players involved in thyroidal homeostasis (TSH, TH, and iodide) on thyroidal dehalogenating enzymes, our results add further insights into their regulation and, hence, contribute to the understanding of fundamental aspects of thyroid physiology.

Blockade of TH synthesis (by MMI+KClO4) caused a sustained increase in TSH, which led, in turn, to significant increases in the activity of both thyroidal enzymes. These results could be interpreted as a direct stimulation by TSH; however, it should be emphasized that besides being hyper-stimulated by TSH, the thyroid glands of this hypothyroid group are deficient in TH and iodide. Thus, any of these three factors could be responsible for the observed changes in enzyme activity. Nevertheless, and as previously showed in cell cultures for tDh (Gnidehou et al. 2004) and ID1 mRNAs (Toyoda et al. 1992), the finding that both enzyme activities increase in HPX animals receiving TSH supports a direct positive effect of this pituitary hormone on the activity of the two intrathyroidal dehalogenases. Furthermore, this TSH stimulatory effect is enhanced when the thyroid gland of HPX animals is iodide-depleted, data that are consistent with the inhibitory effect exerted on both enzymes by either acute or chronic iodide overload.

The differential response of rtDh (decrease) and ID1 (increase) activities in intact animals treated with supraphysiological doses of T3 (hyperthyroidism model) further supports the positive effect of TSH on rtDh. Furthermore, the stimulatory effect of T3 on ID1 activity is demonstrated by its significant increase in HPX animals. The response of ID1 to T3 was expected, because TH-responsive elements are present in the promoter region of the Dio1 gene (Toyoda et al. 1992, Koenig 2005). Similarly, ID1 activity also increased in the kidney and liver of HPX T3-treated rats. Interestingly, in all tissues assayed, ID1 activity increased significantly in HPX TSH-replaced rats. However, this increase was prevented in kidney and liver when endogenous TH synthesis was pharmacologically blocked (MMI+KClO4). Together, these data support the notion that extrathyroidal ID1 is T3 dependent, and they confirm previous studies showing that only thyroidal ID1 is TSH dependent (Erickson et al. 1982). Consistent with their known stimulatory effect on TSH receptor expression (Denereaz & Lemarchand-Beraud 1995), when co-administered to HPX rats, TSH and T3 exerted additive effects on the activity of both intrathyroidal dehalogenases, but not on hepatic or renal ID1 activities. As expected, the level of NIS mRNA decreased in hyperthyroid animals but increased in hypothyroid animals, thus reflecting its regulation by TSH. In addition, NIS mRNA levels also significantly decreased after acute and chronic iodide administration; again, this was the expected response since acute exposure to iodide triggers the Wolff–Chaikoff effect (Eng et al. 1999).

A major finding of the present study consists of the result that the halogen overload (acute and chronic) significantly inhibits the activity and expression of both intrathyroidal dehalogenases when iodide organification is maintained. In this regard, the well-known inhibitory effect exerted by iodide on TSH responsiveness in the thyroid gland (Cochaux et al. 1987) could be related to the observed decrease in the intrathyroidal dehalogenation by blocking TSH stimulation on both enzymes. However, the fact that TSH and T3 circulating levels did not significantly differ from control group suggests an active thyroidal stimulation by TSH in the presence of the halogen, which argues against an inhibition in TSH responsiveness by iodide. In this regard, although there was no significant decrease in T3 circulating levels with iodide administration, lower serum T3 levels were found with the acute iodide administration while compared to the controls, which is in agreement with the inhibition in thyroid hormonogenesis induced by the Wolff–Chaikoff effect. The activity of both enzymes was highest when both iodide uptake and organification were pharmacologically inhibited (the I-depleted model). This was observed in both intact (with elevated TSH circulating levels) and HPX rats (with controlled TSH serum levels), which suggests a TSH- and T3-independent inhibitory effect by iodide upon intrathyroidal dehalogenation. Consistent with this observation, Wang et al. (2009) recently reported a significant decrease in both ID1 activity and mRNA expression in thyroid glands of rats chronically treated (months) with iodide excess in drinking water. The results presented here and the findings by Wang et al. strongly suggest that the iodide inhibitory effect on intrathyroidal dehalogenation represents a pivotal mechanism to ensure thyroid homeostasis during an iodide overload. Specifically, we suggest that the down-regulation of the two dehalogenases contributes to the mechanisms involved in the escape from the Wolff–Chaikoff effect. In addition to the effect on TSH responsiveness, Wolff–Chaikoff effect involves the inhibition in the expression of NIS and TPO, as well as inhibition in H2O2 generation, all of which result in a negative impact on TH hormonogenesis (Cochaux et al. 1987, Corvilain et al. 1988, Laurent et al. 1989, Panneels et al. 1994, Uyttersprot et al. 1997, Eng et al. 1999). Paradoxically, for this inhibition to occur, it is mandatory that iodide uptake and/or organification remain intact; i.e. when TPO is pharmacologically blocked before iodide administration, the Wolff–Chaikoff effect does not occur (van Sande et al. 1975). To explain this paradox, the participation of an unknown inhibitory iodinated compound has been suggested, possibly a lipid derivative like iodolactone or iodohexadecanal (Dugrillon et al. 1990, Panneels et al. 1996). Our results are consistent with these observations because intrathyroidal dehalogenation is not inhibited, but enhanced when iodide uptake and organification are blocked in HPX animals. It is known that for the escape phenomenon to occur, there must be a decrease in the intrathyroidal, inorganic iodide concentration (Eng et al. 1999). Since the intrathyroidal iodide concentration depends on the balance of its uptake (in) and recycling (out), and given that the halogen inhibits rtDh and ID1, our results support the proposal that both intrathyroidal dehalogenases participate in the escape phenomenon from the Wolff–Chaikoff effect, presumably by contributing to a decrease in the total intrathyroidal iodide concentration.

In conclusion, the present results provide additional insights into the complex mechanisms involved in the Wolff–Chaikoff effect and its escape phenomenon. This is the first study that shows a regulatory effect of iodide upon the activity of the intrathyroidal dehalogenases rtDh and ID1, and it underscores the important role of autoregulatory processes within thyroid follicular cells.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was partially supported by grants CoNaCyT 106214, 080420, SEP-PROMEP UAQ-PTC-156, and PAPIIT UNAM IN203409.

Acknowledgements

We are especially grateful to Dr Peter A Kopp for his invaluable advice and suggestions in the preparation of this manuscript. We also thank Dr J Martin Garcia for his help in obtaining the biological samples, and Leonor Casanova and Rafael Silva for their invaluable technical support, and Dr Dorothy Pless for critically reading the manuscript.

References

  • Alvarez-Buylla R, Quintanar Stephano AQ, Quintanar Stephano JL & De Alvarez-Buylla E 1991 Technical note: removal of the unfragmented pituitary gland (hypophysectomy) in the rat. Boletín de Estudios Médicos y Biológicos 39 3338.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anguiano B, Aceves C, Navarro L, Ramirez del Angel A, Luna M, Perera G & Valverde-R C 1991 Neuroendocrine regulation of adrenal 5′-monodeiodination during acute cold exposure in the rat. I. Effects of hypophysectomy. Endocrinology 128 504508 doi:10.1210/endo-128-1-504.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anguiano B, Garcia-Solis P, Delgado G & Aceves C 2007 Uptake and gene expression with antitumoral doses of iodine in thyroid and mammary gland: evidence that chronic administration has no harmful effects. Thyroid 17 851859 doi:10.1089/thy.2007.0122.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bradford M 1976 A rapid and sensitive method for the quantities of protein utilizing the principle of protein-dye binding. Annals of Biochemistry 72 249254 doi:10.1016/0003-2697(76)90527-3.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cahnman HJ 1972 Methods in Investigative and Diagnostic Endocrinology, 1st edn, p 27. Ed SA Berson. New York: American Elsevier..

    • PubMed
    • Export Citation
  • Cochaux P, Van Sande J, Swillens S & Dumont JE 1987 Iodide-induced inhibition of adenylate cyclase activity in horse and dog thyroid. European Journal of Biochemistry 170 435442 doi:10.1111/j.1432-1033.1987.tb13718.x.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Corvilain B, Van Sande J & Dumont JE 1988 Inhibition by iodide of iodide binding to proteins: the "Wolff–Chaikoff" effect is caused by inhibition of H2O2 generation. Biochemical and Biophysical Research Communications 154 12871292 doi:10.1016/0006-291X(88)90279-3.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dai G, Levy O & Carrasco N 1996 Cloning and characterization of the thyroid iodide transporter. Nature 379 458460 doi:10.1038/379458a0.

  • Denereaz N & Lemarchand-Beraud T 1995 Severe but not mild alterations of thyroid function modulate the density of thyroid-stimulating hormone receptors in the rat thyroid gland. Endocrinology 136 16941700 doi:10.1210/en.136.4.1694.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dugrillon A, Bechtner G, Uedelhoven WM, Weber PC & Gärtner R 1990 Evidence that an iodolactone mediates the inhibitory effect of iodine on thyroid cell proliferation but not on adenosine 3′,5′-monophosphate formation. Endocrinology 127 337343 doi:10.1210/endo-127-1-337.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eng PH, Cardona GR, Fang SL, Previti M, Alex S, Carrasco N, Chin WW & Braverman L 1999 Escape from the acute Wolff–Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. Endocrinology 140 34043410 doi:10.1210/en.140.8.3404.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Erickson VJ, Cavalieri RR & Rosenberg LL 1982 Thyroxine-5′-deiodinase of rat thyroid, but not that of liver, is dependent on thyrotropin. Endocrinology 111 434440 doi:10.1210/endo-111-2-434.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gnidehou S, Caillou B, Talbot M, Ohayon R, Kaniewski J, Noël-Hudson MS, Morand S, Agnangji D, Sezan A & Courtin F et al. 2004 Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site. FASEB Journal 18 15741576 doi:10.1096/fj.04-2023fje.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Koenig RJ 2005 Regulation of type 1 iodothyronine deiodinase in health and disease. Thyroid 15 835840 doi:10.1089/thy.2005.15.835.

  • Kopp P & Solis-S JC 2009 Thyroid hormone synthesis. In Clinical Management of Thyroid Disease, 1st edn, pp 113207. Eds Wondisford F, Radovick S. New York: Elsevier.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Laurent E, Mockel J, Takazawa K, Erneux C & Dumont JE 1989 Stimulation of generation of inositol phosphates by carbamylcholine and its inhibition by phorbol esters and iodide in dog thyroid cells. Biochemical Journal 263 795801.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Maayan ML & Rosenberg IN 1963 Effect of injection of thyrotropin upon deiodination of diiodotyrosine by rat thyroid and liver. Endocrinology 73 3844 doi:10.1210/endo-73-1-38.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Morton ME, Chaikoff IL & Rosenfeld S 1944 Inhibiting effect of inorganic iodide on the formation in vitro of thyroxine and diiodotyrosine by surviving thyroid tissue. Journal of Biological Chemistry 154 381387.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Panneels V, Van den Bergen H, Jacoby C, Braekman JC, Van Sande J, Dumont JE & Boeynaems JM 1994 Inhibition of H2O2 production by iodoaldehydes in cultured dog thyroid cells. Molecular and Cellular Endocrinology 102 167176 doi:10.1016/0303-7207(94)90110-4.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Panneels V, Macours P, Van den Bergen H, Braekman JC, Van Sande J & Boeynaems JM 1996 Biosynthesis and metabolism of 2-iodohexadecanal in cultured dog thyroid cells. Journal of Biological Chemistry 271 2300623014 doi:10.1074/jbc.271.38.23006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Plummer HS 1923 Results of administering iodine to patients having exophthalmic goiter. Journal of the American Medical Association 80 19551965.

  • Roche J, Michel O, Michel R, Gorbman A & Lissitzky S 1953 The enzymatic dehalogenation of halogenated tyrosine derivatives by the thyroid gland and its physiological role. II. Biochimica et Biophysica Acta 12 570576 doi:10.1016/0006-3002(53)90189-9.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rokita SE, Adler JM, McTamney PM & Watson JA Jr 2010 Efficient use and recycle of the micronutrient iodide in mammals. Biochimie 92 12271235 doi:10.1016/j.biochi.2010.02.013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • van Sande J, Grenier G, Willems C & Dumont JE 1975 Inhibition by iodide of the activation of the thyroid cyclic 3′,5′-AMP system. Endocrinology 96 781786 doi:10.1210/endo-96-3-781.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Solis-S JC, Villalobos P, Orozco A & Valverde-R C 2004 Comparative kinetic characterization of rat thyroid iodotyrosine dehalogenase and iodothyronine deiodinase type 1. Journal of Endocrinology 181 385392 doi:10.1677/joe.0.1810385.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • St Germain DL, Galton VA & Hernandez A 2009 Minireview: defining the roles of the iodothyronine deiodinases: current concepts and challenges. Endocrinology 150 10971107 doi:10.1210/en.2008-1588.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Toyoda N, Nishikawa M, Mori Y, Gondou A, Ogawa Y, Yonemoto T, Yoshimura M, Masaki H & Inada M 1992 Thyrotropin and triiodothyronine regulate iodothyronine 5′-deiodinase Messenger ribonucleic acid levels in FRTL-5 rat thyroid cells. Endocrinology 131 389394 doi:10.1210/en.131.1.389.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Uyttersprot N, Pelgrims N, Carrasco N, Gervy C, Maenhaut C, Dumont JE & Miot F 1997 Moderate doses of iodide in vivo inhibit cell proliferation and the expression of thyroperoxidase and Na+/I− symporter mRNAs in dog thyroid. Molecular and Cellular Endocrinology 131 195203 doi:10.1016/S0303-7207(97)00108-1.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang K, Sun YN, Liu JY, Zhang L, Ye Y, Lin LX, Yan YQ & Chen ZP 2009 The impact of iodine excess on thyroid hormone biosynthesis and metabolism in rats. Biological Trace Element Research 130 7285 doi:10.1007/s12011-009-8315-z.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wolff J & Chaikoff IL 1948 Plasma inorganic iodide as a homeostatic regulator of thyroid function. Journal of Biological Chemistry 174 555564.

  • Zimmermann MB 2009 Iodine deficiency. Endocrine Reviews 30 376408 doi:10.1210/er.2009-0011.

 

  • Collapse
  • Expand
  • Effect of hypo and hyperthyroidism on rtDh and ID1 activities in the thyroid gland of intact rats. Each bar shows the mean±s.e.m. of three independent enzymatic assays, each performed in duplicate. Asterisks indicate significant differences as compared to control animals (*P<0.05, **P<0.001). Further details are in the text.

  • Effect of acute (24 h) and chronic (7 days) KI load on rtDh and ID1 activities in the thyroid gland of intact rats. Each bar shows the mean±s.e.m. of three independent enzymatic assays performed in duplicate. Asterisks indicate significant differences as compared to control animals (**P<0.001). Further details are in the text.

  • Effect of TSH, MMI/KClO4, and T3 treatments on rtDh and ID1 activities in thyroid glands of HPX rats. Each bar shows the mean±s.e.m. of three independent enzymatic assays performed in duplicate. Different letters indicate significant differences (P<0.05) between the groups. Further details are in the text.

  • Effect of TSH, MMI/KClO4, and T3 treatments on ID1 activity in liver and kidney of HPX rats. Each bar shows the mean±s.e.m. of three independent enzymatic assays performed in duplicate. Comparison between groups was performed by one-way ANOVA followed by Tukey's post hoc tests. Different letters indicate significant differences (P<0.05) between the groups. Further details are in the text.

  • Effect of hypothyroidism, hyperthyroidism, and acute and chronic iodide load on thyroidal mRNA levels of tDH, ID1, and NIS. Results are presented as normalized mRNA levels relative to those of the corresponding control. Actin served as an internal control and was used to normalize for differences in input RNA. Groups not shown (tDH and ID1 for both hyperthyroidism and hypothyroidism) did not differ significantly from their respective controls. Data are expressed as mean±s.e.m. of three independent measurements. Asterisks indicate significant difference from the corresponding controls (**P<0.001).

  • Alvarez-Buylla R, Quintanar Stephano AQ, Quintanar Stephano JL & De Alvarez-Buylla E 1991 Technical note: removal of the unfragmented pituitary gland (hypophysectomy) in the rat. Boletín de Estudios Médicos y Biológicos 39 3338.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anguiano B, Aceves C, Navarro L, Ramirez del Angel A, Luna M, Perera G & Valverde-R C 1991 Neuroendocrine regulation of adrenal 5′-monodeiodination during acute cold exposure in the rat. I. Effects of hypophysectomy. Endocrinology 128 504508 doi:10.1210/endo-128-1-504.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anguiano B, Garcia-Solis P, Delgado G & Aceves C 2007 Uptake and gene expression with antitumoral doses of iodine in thyroid and mammary gland: evidence that chronic administration has no harmful effects. Thyroid 17 851859 doi:10.1089/thy.2007.0122.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bradford M 1976 A rapid and sensitive method for the quantities of protein utilizing the principle of protein-dye binding. Annals of Biochemistry 72 249254 doi:10.1016/0003-2697(76)90527-3.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cahnman HJ 1972 Methods in Investigative and Diagnostic Endocrinology, 1st edn, p 27. Ed SA Berson. New York: American Elsevier..

    • PubMed
    • Export Citation
  • Cochaux P, Van Sande J, Swillens S & Dumont JE 1987 Iodide-induced inhibition of adenylate cyclase activity in horse and dog thyroid. European Journal of Biochemistry 170 435442 doi:10.1111/j.1432-1033.1987.tb13718.x.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Corvilain B, Van Sande J & Dumont JE 1988 Inhibition by iodide of iodide binding to proteins: the "Wolff–Chaikoff" effect is caused by inhibition of H2O2 generation. Biochemical and Biophysical Research Communications 154 12871292 doi:10.1016/0006-291X(88)90279-3.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dai G, Levy O & Carrasco N 1996 Cloning and characterization of the thyroid iodide transporter. Nature 379 458460 doi:10.1038/379458a0.

  • Denereaz N & Lemarchand-Beraud T 1995 Severe but not mild alterations of thyroid function modulate the density of thyroid-stimulating hormone receptors in the rat thyroid gland. Endocrinology 136 16941700 doi:10.1210/en.136.4.1694.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dugrillon A, Bechtner G, Uedelhoven WM, Weber PC & Gärtner R 1990 Evidence that an iodolactone mediates the inhibitory effect of iodine on thyroid cell proliferation but not on adenosine 3′,5′-monophosphate formation. Endocrinology 127 337343 doi:10.1210/endo-127-1-337.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eng PH, Cardona GR, Fang SL, Previti M, Alex S, Carrasco N, Chin WW & Braverman L 1999 Escape from the acute Wolff–Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. Endocrinology 140 34043410 doi:10.1210/en.140.8.3404.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Erickson VJ, Cavalieri RR & Rosenberg LL 1982 Thyroxine-5′-deiodinase of rat thyroid, but not that of liver, is dependent on thyrotropin. Endocrinology 111 434440 doi:10.1210/endo-111-2-434.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gnidehou S, Caillou B, Talbot M, Ohayon R, Kaniewski J, Noël-Hudson MS, Morand S, Agnangji D, Sezan A & Courtin F et al. 2004 Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site. FASEB Journal 18 15741576 doi:10.1096/fj.04-2023fje.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Koenig RJ 2005 Regulation of type 1 iodothyronine deiodinase in health and disease. Thyroid 15 835840 doi:10.1089/thy.2005.15.835.

  • Kopp P & Solis-S JC 2009 Thyroid hormone synthesis. In Clinical Management of Thyroid Disease, 1st edn, pp 113207. Eds Wondisford F, Radovick S. New York: Elsevier.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Laurent E, Mockel J, Takazawa K, Erneux C & Dumont JE 1989 Stimulation of generation of inositol phosphates by carbamylcholine and its inhibition by phorbol esters and iodide in dog thyroid cells. Biochemical Journal 263 795801.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Maayan ML & Rosenberg IN 1963 Effect of injection of thyrotropin upon deiodination of diiodotyrosine by rat thyroid and liver. Endocrinology 73 3844 doi:10.1210/endo-73-1-38.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Morton ME, Chaikoff IL & Rosenfeld S 1944 Inhibiting effect of inorganic iodide on the formation in vitro of thyroxine and diiodotyrosine by surviving thyroid tissue. Journal of Biological Chemistry 154 381387.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Panneels V, Van den Bergen H, Jacoby C, Braekman JC, Van Sande J, Dumont JE & Boeynaems JM 1994 Inhibition of H2O2 production by iodoaldehydes in cultured dog thyroid cells. Molecular and Cellular Endocrinology 102 167176 doi:10.1016/0303-7207(94)90110-4.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Panneels V, Macours P, Van den Bergen H, Braekman JC, Van Sande J & Boeynaems JM 1996 Biosynthesis and metabolism of 2-iodohexadecanal in cultured dog thyroid cells. Journal of Biological Chemistry 271 2300623014 doi:10.1074/jbc.271.38.23006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Plummer HS 1923 Results of administering iodine to patients having exophthalmic goiter. Journal of the American Medical Association 80 19551965.

  • Roche J, Michel O, Michel R, Gorbman A & Lissitzky S 1953 The enzymatic dehalogenation of halogenated tyrosine derivatives by the thyroid gland and its physiological role. II. Biochimica et Biophysica Acta 12 570576 doi:10.1016/0006-3002(53)90189-9.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rokita SE, Adler JM, McTamney PM & Watson JA Jr 2010 Efficient use and recycle of the micronutrient iodide in mammals. Biochimie 92 12271235 doi:10.1016/j.biochi.2010.02.013.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • van Sande J, Grenier G, Willems C & Dumont JE 1975 Inhibition by iodide of the activation of the thyroid cyclic 3′,5′-AMP system. Endocrinology 96 781786 doi:10.1210/endo-96-3-781.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Solis-S JC, Villalobos P, Orozco A & Valverde-R C 2004 Comparative kinetic characterization of rat thyroid iodotyrosine dehalogenase and iodothyronine deiodinase type 1. Journal of Endocrinology 181 385392 doi:10.1677/joe.0.1810385.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • St Germain DL, Galton VA & Hernandez A 2009 Minireview: defining the roles of the iodothyronine deiodinases: current concepts and challenges. Endocrinology 150 10971107 doi:10.1210/en.2008-1588.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Toyoda N, Nishikawa M, Mori Y, Gondou A, Ogawa Y, Yonemoto T, Yoshimura M, Masaki H & Inada M 1992 Thyrotropin and triiodothyronine regulate iodothyronine 5′-deiodinase Messenger ribonucleic acid levels in FRTL-5 rat thyroid cells. Endocrinology 131 389394 doi:10.1210/en.131.1.389.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Uyttersprot N, Pelgrims N, Carrasco N, Gervy C, Maenhaut C, Dumont JE & Miot F 1997 Moderate doses of iodide in vivo inhibit cell proliferation and the expression of thyroperoxidase and Na+/I− symporter mRNAs in dog thyroid. Molecular and Cellular Endocrinology 131 195203 doi:10.1016/S0303-7207(97)00108-1.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang K, Sun YN, Liu JY, Zhang L, Ye Y, Lin LX, Yan YQ & Chen ZP 2009 The impact of iodine excess on thyroid hormone biosynthesis and metabolism in rats. Biological Trace Element Research 130 7285 doi:10.1007/s12011-009-8315-z.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wolff J & Chaikoff IL 1948 Plasma inorganic iodide as a homeostatic regulator of thyroid function. Journal of Biological Chemistry 174 555564.

  • Zimmermann MB 2009 Iodine deficiency. Endocrine Reviews 30 376408 doi:10.1210/er.2009-0011.