Mechanism of thyroid peroxidase inhibition by ethylenethiourea

Doerge, Daniel R.; Takazawa, Richard S.

doi:10.1021/tx00014a003

Cited by 73 publications

(54 citation statements)

References 14 publications

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“…Given this background, we conducted a comparative analysis of the histological and molecular alterations in thyroids of X. laevis tadpoles treated with either PER to inhibit iodide uptake (Wolff, 1998) or ETU to inhibit iodide organification (Doerge and Takazawa, 1990). Results from these analyses confirmed previous observations of different histological phenotypes associated with each of the two treatment regimes (Opitz et al, 2006b).…”

Section: Introductionsupporting

confidence: 65%

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Opitz

Schmidt

Braunbeck

et al. 2009

Molecular and Cellular Endocrinology

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Despite evidence for a conserved role of thyroid-stimulating hormone (TSH) in regulating vertebrate thyroid function, molecular data on thyroid responses to TSH are mainly limited to mammalian species. In this study, we examined histological and molecular changes in the thyroid of Xenopus laevis tadpoles during a 12-day treatment with 20 mg/l perchlorate (PER) and 50 mg/l ethylenethiourea (ETU). Inhibition of thyroid hormone (TH) synthesis by PER and ETU was evident from developmental retardation, reduced expression of TH-regulated genes and up-regulation of tshb-A mRNA. Thyroid histopathology revealed goiters with strikingly different follicular morphologies following PER and ETU treatment. Using real-time PCR, we analyzed thyroids sampled on day 12 for differential expression of 60 candidate genes. Further temporal analyses were performed for a subset of 14 genes. Relative to the control, PER and ETU treatment modulated the expression of 51 and 49 transcripts, respectively. Particularly genes related to TH synthesis and protein metabolism were similarly affected by PER and ETU.However, several genes were differentially expressed in PER-and ETU-treated tadpoles.Specifically, goiter formation in the PER treatment was associated with low expression of genes related to DNA replication but high expression of negative growth regulators. Results from this work provide for the first time a characterization of gene expression profiles during goitrogenesis in a non-mammalian vertebrate model. Overall, our data suggest that, in addition to TSH over-stimulation, further mechanisms related to the mode of goitrogen action contribute to the regulation of thyroid gene expression.

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Section: Introductionsupporting

confidence: 65%

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Opitz

Schmidt

Braunbeck

et al. 2009

Molecular and Cellular Endocrinology

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“…With sodium perchlorate and ETU, we selected two goitrogenic compounds that inhibit thyroid gland function via different modes of action; the perchlorate anion inhibits thyroidal iodide uptake, whereas ETU inhibits organification of iodide (Doerge & Takazawa 1990, Wolff 1998. The test concentrations chosen for these compounds are known to severely suppress TH-dependent development, while inducing thyroid gland hyperplasia in X. laevis tadpoles (Tietge et al 2005, Opitz et al 2006a.…”

Section: Discussionmentioning

confidence: 99%

“…Stage 52 tadpoles were treated with 50 mg/l ETU or 20 mg/l sodium perchlorate for 12 days to study in vivo the effects of TSH overexpression on gene expression in the thyroid gland. Because ETU inhibits iodide organification (Doerge & Takazawa 1990) and perchlorate inhibits thyroidal iodide uptake (Wolff 1998), these treatments were both expected to inhibit TH synthesis, thereby inducing a compensatory rise in TSH production and release. The presence of TH-deficient conditions in the treated tadpoles was assessed via examination of tadpole development, TSHb mRNA expression in pituitary tissue, and thyroid gland histology (Figs 5 and 6).…”

Section: Effects Of Etu and Perchlorate Treatment On Thyroid Gland Gementioning

confidence: 99%

Expression of sodium-iodide symporter mRNA in the thyroid gland of Xenopus laevis tadpoles: developmental expression, effects of antithyroidal compounds, and regulation by TSH

Opitz¹,

Trubiroha²,

Lorenz³

et al. 2006

Journal of Endocrinology

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The uptake of iodide represents the first step in thyroid hormone synthesis by thyroid follicular cells and is mediated by the sodium-iodide symporter (NIS). In mammals, expression of NIS is stimulated by TSH and transcription of the NIS gene involves regulation by the thyroid-specific transcription factors Pax8 and Nkx2$1. In this study, we examined the mRNA expression of NIS, Pax8 and Nkx2$1 in the thyroid gland of Xenopus laevis tadpoles by semiquantitative reverse transcriptase (RT)-PCR. During spontaneous metamorphosis, NIS mRNA expression was low in premetamorphic tadpoles, increased throughout prometamorphosis, and peaked at climax stage 60. Analysis of TSH bsubunit (TSHb) mRNA in the pituitary of the same tadpoles revealed a close temporal relationship in the expression of the two genes during metamorphosis, suggesting a regulatory role of TSH in the developmental expression of NIS. Treatment of tadpoles with goitrogenic compounds (sodium perchlorate and ethylenethiourea) increased TSHb mRNA expression (approximately twofold) and caused thyroid gland hyperplasia, confirming that feedback along the pituitary-thyroid axis was operative. Analysis of gene expression in the thyroid gland revealed that goitrogen treatment was correlated with increased expression of NIS mRNA (w20-fold). In the thyroid gland organ culture experiments, bovine TSH (bTSH; 1 mU/ml) strongly induced NIS mRNA expression. This effect was mimicked by co-culture of thyroid glands with pituitaries from stage 58 tadpoles and by agents that increase intracellular cAMP (forskolin, dibutyryl-cAMP). In addition, it could be shown that thyroid glands of X. laevis tadpoles express Pax8 and Nkx2$1 mRNA in a developmentally regulated manner and that ex vivo treatment of thyroid glands with bTSH, forskolin, and cAMP analogs increased the expression of Pax8 and Nkx2$1 mRNA. This is the first report on developmental profiles and hormonal regulation of thyroid gland gene expression in amphibian tadpoles and, together, results reveal a critical role of TSH in the regulation of NIS mRNA expression in the thyroid gland of X. laevis tadpoles.

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“…Inhibition of LPX activity by 1-111 was determined from the kinetics of oxidation of iodide ion and guaiacol (Doerge, 1986) or ABTS (Mansson-Rahemtulla et al, 1988;Doerge & Takazawa, 1990) assaysconducted at 25 f 0.2 O C . Kinetic parameters of suicide inactivation were determined as previously described (Doerge, 1986).…”

Section: Methodsmentioning

confidence: 99%

Chemical and enzymic oxidation of benzimidazoline-2-thiones: a dichotomy in the mechanism of peroxidase inhibition

Doerge¹,

Decker²,

Takazawa³

1993

Biochemistry

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Derivatives of imidazole-2-thiones block reactions catalyzed by thyroid peroxidase (TPX) and the closely related lactoperoxidase (LPX), and this property is used therapeutically to treat hyperthyroidism. The reactions of a series of benzimidazoline-2-thiones with chemical and enzymatic oxidants were investigated to probe systematically the mechanism of inhibition. Oxidation of benzimidazoline-2-thione (I) and 1-methylbenzimidazoline-2-thione (II) with 3-chloroperbenzoic acid (PBA) yielded reaction products and stoichiometry consistent with benzimidazole-2-sulfenic acids as reactive intermediates. The N,N'-disubstituted nature of 1,3-dimethylbenzimidazoline-2-thione (III) precludes sulfenic acid formation by tautomerization, and the oxidation of III with PBA yielded products and stoichiometry that were consistent with a benzimidazole-2-sulfonyl ylide as the reactive intermediate. I and II are suicide inhibitors of LPX and TPX, but III was found to inhibit only peroxidase-catalyzed iodination reactions by an alternate substrate mechanism. These results provide support for the hypothesis that imidazole-2-sulfenic acids are important reactive intermediates in the suicide inactivation of TPX and LPX and relate the chemical reactivity of the inhibitor with both the potency and mechanism of inhibition. These results suggest that 1,3-disubstituted thiourea derivatives represent a new class of potential antihyperthyroid drugs that block TPX-catalyzed tyrosine iodination but do not cause irreversible enzyme inactivation.

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Mechanism of thyroid peroxidase inhibition by ethylenethiourea

Cited by 73 publications

References 14 publications

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Expression of sodium-iodide symporter mRNA in the thyroid gland of Xenopus laevis tadpoles: developmental expression, effects of antithyroidal compounds, and regulation by TSH

Chemical and enzymic oxidation of benzimidazoline-2-thiones: a dichotomy in the mechanism of peroxidase inhibition

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