1 Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, School of Medicine, and 2 Department of Endocrinology, Erasme University Hospital, Free University of Brussels, 1070 Brussels, Belgium
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ABSTRACT |
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The regulation of thyroid metabolism by iodide involves numerous inhibitory effects. However, in unstimulated dog thyroid slices, a small inconstant stimulatory effect of iodide on H2O2 generation is observed. The only other stimulatory effect reported with iodide is on [1-14C]glucose oxidation, i.e., on the pentose phosphate pathway. Because we have recently demonstrated that the pentose phosphate pathway is controlled by H2O2 generation, we study here the effect of iodide on basal H2O2 generation in thyroid slices from several species. Our data show that in sheep, pig, bovine, and to a lesser extent dog thyroid, iodide had a stimulatory effect on H2O2 generation. In horse and human thyroid, an inconstant effect was observed. We demonstrate in dogs that the stimulatory effect of iodide is greater in thyroids deprived of iodide, raising the possibility that differences in thyroid iodide pool may account, at least in part, for the differences between the different species studied. This represents the first demonstration of an activation by iodide of a specialized thyroid function. In comparison with conditions in which an inhibitory effect of iodide on H2O2 generation is observed, the stimulating effect was observed for lower concentrations and for a shorter incubation time with iodide. Such a dual control of H2O2 generation by iodide has the physiological interest of promoting an efficient oxidation of iodide when the substrate is provided to a deficient gland and of avoiding excessive oxidation of iodide and thus synthesis of thyroid hormones when it is in excess. The activation of H2O2 generation may also explain the well described toxic effect of acute administration of iodide on iodine-depleted thyroids.
Wolff-Chaikoff effect; thyroid hormone synthesis; iodide toxicity; pentose phosphate pathway
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INTRODUCTION |
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THYROID HORMONE SYNTHESIS in the thyroid requires iodide, thyroglobulin, and an oxidation system to oxidize iodide and to iodinate tyrosyl groups in thyroglobulin and couple them into iodothyronines (13, 23). This oxidation system is constituted by a thyroperoxidase that oxidizes iodide in the presence of H2O2 and an ill defined H2O2 generating system using NADPH as coenzyme.
The metabolism of iodide in the thyroid gland makes the most efficient use of an iodine supply that is often scarce and intermittent. But the thyroid also has adaptation mechanisms that reduce iodine metabolism when the supply is abundant, thus avoiding thyrotoxicosis. These include direct inhibitory effects of iodide in the thyroid itself, and inhibition by iodide of its own organification (Wolff-Chaikoff effect), its transport, thyroid hormone secretion, cAMP formation in response to thyroid-stimulating hormone (TSH), and several other metabolic steps (29). We also previously observed an inhibitory effect of iodide on H2O2 generation in response to various agonists. Because, when iodide supply is sufficient, H2O2 generation is the limiting step for iodide organification, it was concluded that the Wolff-Chaikoff effect was caused by the inhibitory effect of iodide on H2O2 generation (11). However, in unstimulated dog thyroid slices, a small inconstant stimulatory effect of iodide on H2O2 generation was observed. Until then, the only stimulatory effect reported with iodide was on [1-14C]glucose oxidation in some species [sheep (14, 18), cattle (17), and to a lesser extent dogs (18, 25)]. This effect was attributed to an increase in the NADP+/NADPH ratio, but its physiological significance was unknown (16).
The present study was initiated to determine whether the small iodide stimulatory effect on H2O2 generation previously observed in dog thyroid was also observed in other species. Because we have demonstrated recently in dog and human thyroid that the activity of the pentose phosphate pathway is controlled by the rate of NADPH oxidation, which itself depends on the rate of H2O2 generation (10, 12), we investigated mainly species in which a stimulatory effect of iodide on [1-14C]glucose oxidation had been demonstrated previously. We analyzed this effect for various iodide concentrations and various kinetics to compare those conditions with those in which the classical inhibitory effect on H2O2 generation is observed. Because it is well known that iodide depletion may influence thyroid response to iodide (6), we also studied in dog thyroids whether the size of the iodine pool, i.e., previous iodine supply, might influence the H2O2 response to iodide. The results suggest that iodide stimulates the generation of its cosubstrate H2O2, which limits its oxidation and thus its own metabolism.
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MATERIALS AND METHODS |
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Products. Horseradish peroxidase type II, homovanillic acid, 12-O-tetradecanoylphorbol 13-acetate (TPA), and bovine TSH were purchased from Sigma Chemical (St. Louis, MO), carbamylcholine from K and K (Plainview, NY), ionomycin from Calbiochem-Berhing (La Jolla, CA), and forskolin (FSK) from Hoechst Pharmaceuticals (Bombay, India). All other reagents were of the purest grade commercially available.
Tissues. Human thyroid tissue was obtained from euthyroid patients undergoing lobectomies for resection of solitary cold nodules. Only the healthy normal-looking nonnodular tissue was used within 10-30 min of surgical resection.
Sheep, pig, bovine, and horse thyroids were obtained from freshly killed animals at a local slaughterhouse. Dog thyroids were obtained from dogs ±10 kg otherwise used for cardiological experiments. Dogs with decreased iodide pool were obtained and treated for 6 wk with propylthiouracil (2 × 150 mg/day), strumazol (2 × 80 mg/day), and NaClO4 (2 × 1 g/day). Not to interfere with iodide metabolism during the experiment, treatment with propylthiouracil and strumazol was stopped 48 h before and the treatment with NaClO4 24 h before the experiment. On the day of the experiment, dogs were anesthetized with pentobarbital, and the thyroid lobes were resected. Thyroids were cut into thin slices of ~50 mg wet weight (wet wt) with a Stadie-Riggs microtome.H2O2 determinations. Slices were preincubated in Krebs-Ringer HEPES (KRH) medium supplemented with 8 mM glucose and 0.5 g/l of BSA and then transferred to fresh medium containing 0.1 mg/ml horseradish peroxidase type II, 440 µM homovanillic acid, and the tested agonists. The fluorescence of the medium was measured 90 min later except when stipulated otherwise (315 and 425 nm excitation and emission wavelengths respectively) (2).
cAMP measurements. Slices were preincubated at 37°C for 1 h under an atmosphere of 95% O2-5% CO2 (vol/vol) in 2 ml of Krebs-Ringer bicarbonate (KRB) supplemented with 8 mM glucose and 0.5 g/l of BSA. For the test incubation of 1 h, medium was supplemented with 100 µM Ro 20-1724, a cAMP-specific phosphodiesterase inhibitor (22). cAMP was measured according to Brooker et al. (7).
Inositol phosphate measurements. Slices were preincubated for 4 h at 37°C in a medium similar to cAMP measurements but with 20 µCi/ml 3H-labeled inositol (specific activity 10-20 Ci/mmol, Amersham). The slices were then transferred to fresh unlabeled medium to which 10 mM lithium was added after 15 min. After an additional 5 min, the tested agents were added. The [3H]inositol phosphates were isolated by stepwise chromatography on a AG1-X8 resin (formate form, 100-200 µm mesh; Biorad, Watford, UK) Incorporation of [3H]inositol into the total phosphatidylinositide pool was quantitated after chloroform/methanol extraction of lipids from the pellet (3). Results are expressed as the percentage of radioactivity incorporated in inositol phosphates (IP1 + IP2 + IP3) over the sum of radioactivity in inositol phosphates and phosphatidylinositol.
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RESULTS |
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Effect of iodide on H2O2 generation in
human, horse, sheep, and dog thyroid slices.
The initial experiments were performed on human thyroid slices
and thyroid from three animal species. Various concentrations of iodide
were added in the preincubation and incubation media for experiments
performed on human, horse, and dog thyroid and only in the incubation
medium for those performed on sheep thyroid. As shown in Table
1, the iodide effect on basal
H2O2 generation depends on the species
considered. In human and horse thyroid slices, iodide had only a small
and inconstant stimulatory effect on H2O2
generation. In human thyroid slices, the basal production of
H2O2 was very low and frequently below the
detection limit. Only experiments in which the basal production of
H2O2 was estimated to be reliable were taken
into account (>20 ng
H2O2 · 100 mg wet wt1 · 120 min
1). Stimulation by iodide was
significant in two experiments out of five with a maximal stimulation
of 210% for an iodide concentration of
10
5 M. However, when all the experiments
were pooled, the effect of iodide on H2O2
generation was not statistically significant whatever the concentration
used. The same level of stimulation without statistically significant
results was obtained in horse thyroid slices. In dog thyroid slices,
iodide had a small but constant stimulatory effect on
H2O2 generation. This effect was maximal for an
iodide concentration of 10
5 M but
remained weak compared with that obtained with 10 mU/ml TSH. In sheep
thyroid slices, an iodide concentration of
10
4 M nearly doubled
H2O2 generation, which reached >50% of the
value obtained with 10 mU/ml TSH. In all species, this stimulation was prevented by adding methimazole (10
4 M)
to the preincubation and incubation media.
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Effect of increasing time of preincubation with iodide on
H2O2 generation.
The data presented in Table 1 clearly show that the effect of
iodide on H2O2 generation is
dependent on its concentration and on the species studied. Because in
human thyroid the basal level of H2O2
generation was too frequently below the detection limit, further
experiments were performed on other species. The following set of
experiments was performed to evaluate the kinetics of this effect in
the three previous species and in two others (pig and bovine). The
concentration of iodide for which the maximal stimulatory effect had
been observed was used for those experiments (105 M for dog thyroid experiments and
10
4 M for other species). In all species
but horse, preincubation with iodide increased its stimulatory effect
on H2O2 generation. In horse thyroid slices,
even a preincubation of 4 h did not increase its stimulatory effect
(data not shown). In bovine thyroid slices, a preincubation of 4 h
results in a quite undetectable basal level of
H2O2 generation. The maximal measurable
stimulation was therefore obtained after 2 h of preincubation and
reached 444 ± 220% for an iodide concentration of
10
4 M (P < 0.05). In three
species (dog, pig, and sheep) the kinetics of the iodide effect on
H2O2 generation were analyzed in more detail
(Fig. 1). In dog and pig thyroid slices,
the maximal effect was nearly reached after 1 h of preincubation with
iodide. Further increase of the length of preincubation resulted in
only a minor additional increase of H2O2
generation. After 4 h of preincubation, the maximal effect reached
186.9 ± 18.3% of the control value in dog thyroid slices and 408 ± 58% of the control in pig thyroid slices. In sheep thyroid slices, the
kinetic of preincubation with iodide showed a progressive increase of
H2O2 generation with the time of preincubation.
H2O2 generation after 4 h of preincubation reached 606 ± 76% of the control value. Compared with the
stimulation obtained by TSH, the iodide stimulatory effect is weak in
dog thyroids and of the same order of magnitude or even more potent in
pig and sheep thyroid, respectively. As previously demonstrated, iodide
inhibited H2O2 generation in dog TSH-stimulated
slices (11), whereas in sheep and pig TSH-stimulated slices, iodide induced a further increase of H2O2 generation.
Both effects were reversed in the presence of methimazole.
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Effect of increasing iodide concentrations on
H2O2 generation in dog and pig thyroid slices
after preincubation of 4 h in presence of iodide.
Because we had shown that increasing the time of preincubation may
increase the stimulatory effect of iodide, we studied the effect of
various concentrations of iodide after a preincubation of 4 h. Contrary
to observations made with 1 h of preincubation, in dog thyroid, after 4 h of preincubation, H2O2 generation exhibited a
biphasic curve in the presence of an increasing concentration of iodide
(Fig. 2). As already shown in Fig. 1, a
significant stimulatory effect of iodide could be obtained for an
iodide concentration of 105 M. However,
for a higher concentration of iodide, an inhibitory effect on
H2O2 generation was observed that became
statistically significant for an iodide concentration of
10
3 M. This effect was also reversed in
the presence of methimazole. The situation was quite different in pig
thyroid slices, where no inhibitory action of iodide after a 4-h
preincubation was observed whatever the concentration of iodide used.
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Effect of increasing time of preincubation with high concentration
of iodide on H2O2 generation in dog thyroid
slices.
In the presence of high concentrations of iodide (3 × 104 M), H2O2
generation exhibited a biphasic curve when plotted against the time of
preincubation (Fig. 3). The production of
H2O2 was maximal after 1 h of preincubation
with iodide (136 ± 13% of the basal level) and then decreased to
reach a maximal inhibition after 6 h (55 ± 10% of the basal level).
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Effects of agents controlling either phosphatidylinositol
P2 or cAMP cascade on generation of
H2O2 in sheep, pig, and dog thyroid slices.
FSK was chosen to test the role of the cAMP cascade. Carbamylcholine
was chosen to test the role of the whole phospatidylinositol 4,5 biphosphate (PIP2) cascade. Ionomycin, a divalent cation
ionophore that allows extracellular Ca2+ to enter the
cells, and TPA, a pharmacological probe for diacylglycerol-regulated protein kinase C, were used to assess the separate effects
of the activation of each branch of the PIP2 cascade. In
sheep thyroid slices, activation of the PIP2 cascade by
carbamylcholine, enhancement of Ca2+
intracellular levels by ionophore, and activation of protein kinase C
by TPA all stimulated H2O2 generation.
Conversely, the agents stimulating the cAMP cascade exerted an
insignificant inhibition on H2O2 generation.
TSH had a biphasic effect, inhibiting H2O2 generation at 1 mU/ml and increasing it at 10 mU/ml. Such biphasic effects previously observed in human thyroid slices corresponded to the
stimulation of the cAMP cascade at the lower concentration of TSH and
of the PIP2-phospholipase C (PLC) cascade at the higher concentration, respectively (10). In pig thyroid,
H2O2 generation was stimulated by low
concentration of TSH (1 mU/ml), an insignificant stimulating effect was
observed with FSK, and no effect was observed with carbamylcholine. In
dog thyroid slices, as previously described (12),
H2O2 generation was stimulated by both the cAMP
cascade and the PIP2-PLC cascade (Table
2).
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Effect of iodide on PIP2 cascade in sheep, pig, and dog
thyroid slices.
Because H2O2 generation in sheep and pig
thyroid is controlled by the PIP2 cascade, we studied here
the effect of iodide on the [3H]inositol
phosphate generation in those two species. Iodide
(104 M) in the preincubation and
incubation media did not modify [3H]inositol
phosphate generation, whereas the effect of iodide on
H2O2 generation in sheep and pig thyroid was
clearly demonstrated. In the same set of experiments, 10 mU/ml TSH in
pig and 10
5 M carbachol in sheep were
moderate and potent stimulators, respectively, of the PIP2
cascade. Even though both cascades positively control H2O2 generation in dog thyroid slices, we
decided to test the effect of iodide only on the PIP2
cascade because it had already been demonstrated in this species that
iodide does not stimulate basal cAMP generation (26); iodide does not
stimulate the PIP2 cascade either (Table
3).
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Effect of iodide on cAMP cascade in sheep thyroid slices.
Iodide (105 M) added during the 1-h
preincubation and during the incubation decreased basal cAMP generation
from 85.7 ± 10.1 pmol · 100 mg wet
wt
1 · 60 min
1 in control slices to 61.3 ± 6.1 pmol · 100 mg wet
wt
1 · 60 min
1 in iodide-treated slices (P < 0.05).
Effect of thyroid iodine pool on H2O2
generation induced by iodide.
Dogs with depleted thyroid iodine pool were obtained as described in
MATERIALS AND METHODS. Other dogs were obtained and treated with 1 ml lipiodol intramuscularly (480 mg iodine/ml) 10 days before
the experiment to increase the thyroid iodine pool. As shown in Fig.
4, the stimulatory effect of iodide on
H2O2 generation was dependent on the iodine
status of the gland. In comparison with control thyroids, in
iodine-depleted thyroids the H2O2 response to
iodide was stronger and more sensitive, starting at
106 M, peaking at 3 × 10
6 M, and then decreasing. The maximal
stimulation was 322 ± 55% of the control value and nearly reached
the value obtained with 10 mU/ml TSH (478 ± 168% of the control
value). In dogs treated with lipiodol, no effect whatever of iodide was
observed with the iodide concentration used.
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Effect of washing with or without methimazole on stimulatory effect
of iodide on H2O2 generation in pig thyroid
slices.
All the slices were preincubated for 2 h in the presence of iodide
(104 M) and then washed for 15 min in
KRH to remove excess iodide. H2O2 generation
was determined either immediately or after additional washing with or
without methimazole for a period of time ranging from 1 to 20 h. When
the washing was done without methimazole, the stimulatory effect of
iodide decreased with time but was still present after 5 h. In the
presence of methimazole, the effect of iodide decreased more rapidly
and disappeared after 3 h. After a washing period of 20 h, a strong
inhibitory effect of iodide on H2O2 generation
could be observed. This effect is partially relieved if the washing has
been done in the presence of methimazole (P < 0.01) (Fig.
5).
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DISCUSSION |
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Thyroid hormone synthesis is characterized by the requirement of a
scarce substrate (iodide) and a toxic cofactor
(H2O2). The thyroid cell generates large
amounts of H2O2, which is toxic for any cell
because of its transformation into various
O2-derived free radicals (9, 19, 28).
A process of apoptosis has also recently been described in vitro when
the thyrocyte is exposed to H2O2 (24). The
thyroid cell protects itself by regulating its production of
H2O2 according to what is required for thyroid hormone synthesis. It is able to increase its
H2O2 production up to 10-fold in the presence
of a high concentration of TSH or other agents that stimulate thyroid
metabolism. H2O2 not used for thyroid hormone
synthesis is destroyed in the thyroid, as in other cells, by several
enzymes of the glutathione peroxidase family and by catalase (5). We
had already demonstrated that large concentrations of iodide inhibited
the H2O2 generation stimulated by various
agonists, but until now, a possible action of iodide on basal
H2O2 production had never been thoroughly
investigated. All the effects of iodide on thyroid metabolism described
so far are inhibitory, apart from the effect on glucose metabolism.
Actually, various data had already demonstrated a stimulatory effect of iodide on basal [1-14C]glucose oxidation in
several species [strong in sheep and bovine thyroid (18, 14, 17),
weaker in dog thyroid (18, 25)]. The present data establish that
iodide can also stimulate H2O2 generation in
several species. This observation is consistent with our previous data
showing that [1-14C]glucose oxidation in dog
and human thyroids is controlled by the rate of
H2O2 generation (12, 10). The magnitude of the iodide effect was greatly dependent on the species under study and the
experimental conditions. As expected, sensitivity to the effect of
iodide on H2O2 generation was maximal in sheep,
the species known to be the most sensitive to its effect on
[1-14C]glucose oxidation. The stimulatory
effect was also strong in pig and bovine thyroid but weaker in human,
dog, and horse thyroid. The stimulatory effect of iodide on
H2O2 generation was prevented by methimazole,
suggesting that it is mediated by an oxidative derivative of iodide.
Apart from the fact that both require a functional iodide oxidation
system, the stimulatory and inhibitory effects of iodide are clearly
distinct; they are species dependent, observable in different
experimental conditions, and have an opposite physiological meaning.
In some species (pig and sheep), the stimulatory effect of iodide
predominates, and demonstration of the inhibitory effect requires
special experimental procedures such as an increased incubation time.
In those species, the strong iodide stimulation on
H2O2 generation further increases the effect of
TSH. Conversely, in other species (dog and human), the inhibitory
effect predominates and the stimulatory effect of iodide is weaker. In
these species, iodide inhibits the effect of TSH on
H2O2 generation, as demonstrated here and
previously (10, 12). This inhibition was attributed to the strong
inhibitory effect of iodide on the activation of the cAMP cascade by
TSH upstream and downstream of cAMP (10, 12). In species where both
effects coexist, the inhibitory effect is observed earlier and for
lower iodide concentrations. In dog thyroid, for a given preincubation
time with iodide, iodide can stimulate or inhibit basal production of
H2O2 according to its concentration. In the
same experimental system, we had previously shown that high
concentrations of iodide (>104 M) are
needed to demonstrate the Wolff-Chaikoff effect (11), the same as the
concentration needed here to inhibit the basal production of
H2O2 and a concentration 100 times higher than
the concentration needed to observe a stimulatory effect. Finally, in
dog and pig thyroid, the first stimulatory effect is followed much
later by an inhibition. In dog thyroid, iodide can stimulate or
inhibit basal production according to the length of preincubation with
iodide. In pig thyroid slices, when the stimulatory effect of iodide is
initiated, it persists after 5 h of washing in the absence of iodide.
However, after 20 h of washing, an inhibitory effect can be observed,
suggesting a late synthesis of an inhibitory compound. Because the
inhibitory effect is partially relieved when the washing is done in the
presence of methimazole, this suggests that the synthesis of this
inhibitory compound requires a functional peroxidase.
The physiological role of the stimulatory and inhibitory effects is also different. Inhibition by excess iodide of H2O2 generation and, therefore, of iodide oxidation and thyroid hormone synthesis is a rapid mechanism to prevent excessive thyroid hormone secretion. It precedes the later classical negative feedback mechanism of excess thyroid hormones on TSH secretion and thyroid stimulation. On the other hand, activation of H2O2 generation at low concentrations of iodide, especially in iodide-deficient animals, will tie the generation of the toxic but necessary H2O2 with the availability of substrate and thus could represent a remarkable adaptation mechanism. Activation or induction of the enzymes necessary for the metabolism of a substrate by the substrate itself is a widespread strategy in bacterial and eukaryote metabolism.
To test this hypothesis we attempted in the current study to evaluate the extent to which iodide depletion or repletion may influence the H2O2 response of the gland to a small iodide load. Compared with control dogs, the effect of iodide on H2O2 generation was strongly increased in thyroid with a decreased iodine pool but was absent in thyroid with an increased iodine pool. This suggests that thyroid iodide content is a major determinant of the H2O2 response of the gland to a small iodide load. However, we cannot exclude the possibility that other mechanisms may play a role, because in our model, iodine deprivation coexists with hypothyroidism and chronic stimulation by TSH.
We therefore addressed the question of the mechanisms involved in this action of iodide. As a first step, we defined, by using various agonists, which cascade is implicated in the control of H2O2 generation in sheep and pig thyroid. The present data establish that in sheep thyroid, as already observed in human (10), calf (20), and pig thyroid (4), H2O2 generation is activated only by the PIP2 cascade, whereas in these species the cAMP cascade has an unimportant (4) or even an inhibitory effect on H2O2 generation (10, 20). As already described, both cascades activate H2O2 generation in dog thyroid slices (12). We could not observe any effect of iodide on the PIP2 cascade in pig, sheep, and dog thyroid. It is unlikely, therefore, that the action of iodide on basal H2O2 generation is mediated by an activation of the PIP2 cascade. Iodide inhibited basal cAMP generation in sheep thyroid slices. Because cAMP exerts a small negative control on H2O2 generation in sheep thyroid, iodide may partly stimulate H2O2 generation by relieving this negative control. Even if this mechanism possibly plays a role in sheep thyroid, it cannot be involved in dog thyroid, in which the cAMP cascade positively controls H2O2 generation, or in pig thyroid, where cAMP cascade does not exert a negative control. It is possible that other untested metabolic pathways could be involved; therefore, the classical metabolic cascades are not involved in the stimulatory effect of iodide, contrary to what was observed previously for the inhibitory effect of iodide on H2O2 generation that obtains both at the level of intracellular signal generation and at the level of the H2O2 generating system (10, 12). This effect of iodide, like many others, is inhibited by methimazole, which suggests that the effect is not direct but is secondary to the generation of an oxidized form of iodine, previously called X-I (27).
Conversely, it is also possible that in vivo, the increase in H2O2 synthesis induced by iodide in iodine-depleted thyroid may have a toxic role in the cell. A necrosis of follicular cells was already described after administration of iodide to iodine-deficient dogs but not to control dogs (1). A necrotizing effect of iodide was also described in iodine-deficient rats and mice (8, 21). The toxicity of iodide was aggravated in cases of selenium deficiency, a circumstance in which defenses against H2O2 are reduced due to a decreased activity of glutathione peroxidase (8). Our data are in keeping with the hypothesis that some of these toxic effects induced by iodide in iodide-deficient thyroids may be partly related to the toxicity of H2O2.
In conclusion, iodide stimulates H2O2 generation in several species. Our experiments suggest that in dog, bovine, and sheep thyroid, the previously observed iodide stimulatory effect on [1-14C]glucose oxidation actually results from an increased H2O2 generation through NADPH oxidation by the still unknown H2O2 generating system. As for [1-14C]glucose oxidation, great interspecies variation exists. The stimulatory effect was greater in sheep, pig, and bovine than in dog thyroids and inconstant in human and horse thyroids. This may be due to either genetic or environmental factors; however, because we demonstrated in dog thyroid that iodide pool greatly influences the H2O2 response to iodide, it seems quite possible that different diets may account, at least in part, for differences between species. Whatever the mechanism involved, the stimulatory action of iodide on H2O2 generation makes physiological sense. In the absence of iodide, there is no need to generate toxic H2O2. Conversely, in its presence, increased H2O2 generation stimulates a more efficient oxidation of iodide. When compared with the inhibitory actions of iodide, this effect is obtained earlier and for lower concentrations, suggesting a physiological role at least as important as that attributed to the classical inhibitory effects. All our results can be viewed teleologically as a means of gearing H2O2 generation to iodide supply. However, when the iodine thyroid pool is or becomes sufficient, as in dogs treated with lipiodol or after long preincubation time with iodide or for high concentration of iodide, the thyroid protects itself against excess iodine organification by decreasing H2O2 production, in keeping with the classical Wolff-Chaikoff effect.
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ACKNOWLEDGEMENTS |
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We thank C. Maenhaut for organization of the in vivo treatments and C. Massart for excellent technical help.
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FOOTNOTES |
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This work was supported by the Fonds de la Recherche Scientifique Médicale, the Ministère de la Politique Scientifique (PAI) and the Fondation Tournai-Solvay.
B. Corvilain is a fellow of the Erasmus Foundation (ULB, Brussels).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: B. Corvilain, IRIBHN, School of Medicine, Campus Erasme, Bat C, Route de Lennik 808, 1070 Brussels, Belgium (E-mail: bcorvila{at}ulb.ac.be).
Received 28 May 1999; accepted in final form 12 November 1999.
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