Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.11.1.8 (thyroid peroxidase)
 3,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied a wide variety of surgical patients to determine whether serum levels of interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-alpha) correlate with the changes in serum thyroid hormone levels of the postoperative period. Surgical procedures were divided into minor surgery (cholecystectomy, n = 12), moderate surgery (colorectal cancer and stomach cancer, n = 54), and extensive surgery (esophageal cancer or pancreatic cancer, n = 6). One day after surgery, serum free T3 levels decreased in all 3 groups when compared to the preoperative values; serum free T4 levels did not change regardless of surgical procedure. Serum TSH levels decreased significantly 1 day after surgery in the groups of moderate and extensive surgery. Serum levels of IL-6 increased 12 h after surgery and began to decrease gradually thereafter. There was no change in serum levels of TNF-alpha before and after surgery. The increment of serum IL-6 was dependent on the surgical procedures: the more extensive the surgery, the greater the increase in serum IL-6. Serum free T3 and free T4 levels were inversely correlated with the serum levels of IL-6. To further examine whether IL-6 is responsible for alteration of thyroid hormone production, cultured porcine thyroid follicles were exposed to 0 to 20 ng/ml of recombinant human IL-6 for 24 to 48 h. Then, type 1 5'-deiodinase activity (T4 to T3 converting enzyme), iodide uptake, and thyroid peroxidase (TPO) activity were measured. Our in vitro experiments showed no effect of IL-6 on these parameters. In summary, surgical procedure can cause elevation of serum IL-6 and decrease in serum free T3 levels. However, IL-6 alone does not appear to be a strong candidate for alteration of thyroid hormone production including T3 generation from T4.
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PMID:Elevated serum interleukin-6 and decreased thyroid hormone levels in postoperative patients and effects of IL-6 on thyroid cell function in vitro. 900 Nov 95

Administration of minocycline (MN), a tetracycline antibiotic, produces a black pigment in the thyroids of humans and several species of experimental animals and antithyroid effects in rodents. We have previously shown that these effects appear to be related to interactions of MN with thyroid peroxidase (TPO), the key enzyme in thyroid hormone synthesis. In the present study, the mechanisms for inhibition of TPO-catalyzed iodination and coupling reactions by MN were investigated. MN was stable in the presence of TPO and H2O2, but adding iodide or a phenolic cosubstrate caused rapid conversion to several products. TPO-dependent product formation, characterized by on-line LC-APCI/MS and 1H-NMR, involved oxidative elimination to form the corresponding benzoquinone with subsequent dehydrogenation at the aliphatic 4-(dimethylamino) group. Addition of thiol-containing polymers (bovine serum albumin or thiol-agarose chromatographic beads) had a minimal effect on MN oxidation by TPO, but substantially reduced product formation and produced concomitant losses in free thiols. Covalent bonding through a thioether linkage of a reactive intermediate, the benzoquinone iminium ion, was inferred from these findings. Iodide- and phenolic cosubstrate-dependent oxidation of tetracycline to demethylated and dehydrogenated products was also observed, although at a slower rate than MN. The products and kinetics observed with MN were consistent with oxidation of MN by either the enzymatic iodinating species formed by reaction of TPO compound I with iodide or phenoxyl radicals/cations generated by TPO-mediated oxidation of a phenolic cosubstrate. The proposed reaction mechanism is consistent with alternate substrate inhibition of TPO-catalyzed iodination of tyrosyl residues in thyroglobulin (Tg) by MN, as previously reported. Furthermore, the observed phenoxyl radical-mediated oxidation of MN is consistent with its previously reported potent inhibition of the coupling of hormonogenic iodotyrosine residues in Tg in the reaction that forms thyroid hormones. The proposed reaction mechanism also implicates a reactive benzoquinone iminium ion intermediate that could be important in toxicity of MN.
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PMID:Mechanism for the anti-thyroid action of minocycline. 907 2

The soybean has been implicated in diet-induced goiter by many studies. The extensive consumption of soy products in infant formulas and in vegetarian diets makes it essential to define the goitrogenic potential. In this report, it was observed that an acidic methanolic extract of soybeans contains compounds that inhibit thyroid peroxidase- (TPO) catalyzed reactions essential to thyroid hormone synthesis. Analysis of the soybean extract using HPLC, UV-VIS spectrophotometry, and LC-MS led to identification of the isoflavones genistein and daidzein as major components by direct comparison with authentic standard reference isoflavones. HPLC fractionation and enzymatic assay of the soybean extract showed that the components responsible for inhibition of TPO-catalyzed reactions coeluted with daidzein and genistein. In the presence of iodide ion, genistein and daidzein blocked TPO-catalyzed tyrosine iodination by acting as alternate substrates, yielding mono-, di-, and triiodoisoflavones. Genistein also inhibited thyroxine synthesis using iodinated casein or human goiter thyroglobulin as substrates for the coupling reaction. Incubation of either isoflavone with TPO in the presence of H2O2 caused irreversible inactivation of the enzyme; however, the presence of iodide ion in the incubations completely abolished the inactivation. The IC50 values for inhibition of TPO-catalyzed reactions by genistein and daidzein were ca. 1-10 microM, concentrations that approach the total isoflavone levels (ca. 1 microM) previously measured in plasma from humans consuming soy products. Because inhibition of thyroid hormone synthesis can induce goiter and thyroid neoplasia in rodents, delineation of anti-thyroid mechanisms for soy isoflavones may be important for extrapolating goitrogenic hazards identified in chronic rodent bioassays to humans consuming soy products.
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PMID:Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action. 946 51

In this study we report on a novel natural target of the paired domain transcription factor PAX 8 in the enhancer element of the human thyroperoxidase gene, one of the most important thyroid differentiation markers. It is the primary enzyme involved in thyroid hormone synthesis and PAX 8 has been previously identified as an activating factor of the rat thyroperoxidase gene promoter. In vitro, PAX 8 binds a cis element of the human enhancer and its exogenous expression induces the enhancer activity in co-transfection experiments in Cos-7 cells. When mutated at this binding site, the enhancer is no longer activated by PAX 8. Our finding strengthens the PAX 8 role in the maintenance of thyroid differentiation and in particular in the tissue-specific thyroperoxidase gene expression.
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PMID:PAX 8 activates the enhancer of the human thyroperoxidase gene. 951 59

Our laboratory has reported suppression of experimental autoimmune thyroiditis in mice by oral feeding with antigen. Based on these data, we considered it possible that oral feeding of animal thyroglobulin (TG) might induce tolerance to antigen in human autoimmune thyroid disease (AITD). Thirteen patients receiving thyroid hormone replacement with synthetic thyroxine (T4) (five patients with Graves' disease, treated with radioiodine 4 to 11 years ago and eight patients with Hashimoto's thyroiditis) were randomly assigned to a test group (switched to replacement with desiccated thyroid from porcine thyroids) and a control group (maintained on synthetic T4). Humoral and cellular immunologic parameters were evaluated in addition to clinical parameters before and every 3 months after the onset of study for a year. At the onset of study, there was no difference in clinical parameters, or humoral and cellular immunity to thyroid autoantigens, except a finding that one thyroid peroxidase (TPO) peptide (100 approximately 119) appeared to stimulate peripheral blood mononuclear cells (PBMC) during in vitro microproliferation assay more in the test group than control group (p = 0.051 by t test). Additionally, almost all of TPO and thyrotropin receptor extracellular domain (TSHR) peptides were slightly more stimulatory to PBMC from the test group than the control group, although this was not statistically significant. After treatment, all variables were analyzed at each time point between groups (t test), and also were analyzed over time in each group (analysis of variance, ANOVA). Among the clinical parameters, thyrotropin (TSH) levels were unchanged and equal. Total serum T4 levels (p < 0.05 at 6 and 12 months after treatment) and free thyroxine indices (FT4I) (p < 0.05 at all time points after treatment) were lower in the test group than the control group. This is an expected result of treatment with desiccated thyroid. We found no change over time nor any difference between groups at time points for titers of antibodies to thyroid autoantigens, ie, human TG, human TPO, and recombinant human TSHR from Escherichia coli. However, cellular immunity, measured by in vitro microproliferation of PBMC to peptides of TPO or TSHR, showed significant differences between groups. At 12 months, stimulatory indices (SI) of PBMC to six peptides, containing the indicated amino acids (764 approximately 95, 100 approximately 119, 110 approximately 129, 261 approximately 275, 441 approximately 448, 708 approximately 727) of 10 TPO peptides, and one peptide (145 approximately 163) of 14 TSHR peptides were lower in the test group than control group (p < 0.05). SI of PBMC to phytohemagglutinin, purified protein derivative from mycobacteria, and tetanus toxoid were not different between groups nor changed over time in any group. In conclusion, treating patients with AITD with an antigen related to the autoantigen TG did not produce changes in humoral immunity parameters, while cellular immunity to certain peptides were apparently suppressed. While the results are both surprising and intriguing, we need more evidence to justify the use of autoantigen as a form of immunospecific therapy in patients with AITD.
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PMID:Induction of oral tolerance in human autoimmune thyroid disease. 954 9

Some widely used psychoactive drugs, such as tricyclic antidepressants and antipsychotic phenothiazines exhibit iatrogenic effects on the thyroid. These side effects may arise from interactions at different steps of thyroid hormone biosynthesis. These drugs can induce a change in iodine capture by thyroid cells or can complex iodine, making it unavailable for thyroid hormone synthesis and thus decreasing thyroid hormone blood levels; they can also inhibit thyroid peroxidase activity and thus T3 and T4 synthesis or enhance deiodination of T4 to T3 or to Rt3 by stimulation of deiodinase activity. Moreover, tricyclic antidepressants interfere with the hypothalamic-pituitary-thyroid axis via the noradrenergic or serotonergic systems and might therefore decrease T4 or T3 blood levels, respectively. Phenothiazines can induce autoimmune hypothyroidism, as shown by an increase in the expression of the major histocompatibility complex antigen and by a production of antithyroglobulin or antithyroperoxidase antibodies. However, all these mechanisms are only speculative in humans, as they have only been demonstrated in vitro or in animal experiments. Clinically, thyroid function and affective disorders are closely linked. On one hand, the therapeutic response to antidepressants could be influenced by the thyroid status; on the other hand, the larger the thyroxin decrease induced by antidepressants, the better the therapeutic effect might be. Moreover, cotreatment with thyroid hormones and antidepressant drugs could allow either a decrease in the rate of treatment failure or a faster recovery from depression. As antipsychotic or antidepressant treatments are administered over long periods in humans, their thyroid toxic effects must be taken seriously.
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PMID:Relationship between psychotropic drugs and thyroid function: a review. 957 80

This study investigated the influence of starvation over seven days on avian thyroidal superoxide radical levels and superoxide dismutase activity profiles in the Indian rock pigeon Columba livia intermeida, in relation with iodine metabolism. The serum thyroid hormone profile was assayed to correlate the thyroidal redox status with the circulating thyroid hormone levels. The spin-trapping results suggest a role for thyroidal superoxide anion (O2.-) in causing a hypothyroid state in pigeons during long term energy withdrawal. Pigeons starved for 1 day generated superoxide and iodide free radicals in their thyroids, with a significant decrease in SOD activity. Regain of SOD activity in 2nd- and 3rd-day starved birds is marked by complete scavenging of radicals in the thyroid, suggesting the significance of SOD in thyroid glands as a potential antioxidant sink against reactive oxygen species, O2.- Resurgence of O2.- radicals with a parallel decrease in SOD activity in the thyroid gland on 5th- and 7th-day of starvation provides evidence of disruption of homeostasis between pro-oxidant and antioxidant states, leading to oxidative stress in avian thyroid during long-term calorie crisis. Following starvation both thyroid hormones thyroxine (T4) and triiodothyronine (T3) decreased, putting pigeons in a hypothyroid state. We argue that oxidative inactivation of thyroid peroxidase and other thyroid proteins by radical attack during starvation invoked oxidative stress, which could be one of the factors responsible for the hypothyroid state in pigeons.
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PMID:Starvation induced hypothyroidism involves perturbations in thyroid superoxide-SOD system in pigeons. 963 31

Thyroglobulin (TG), the primary synthetic product of the thyroid, is the macromolecular precursor of thyroid hormones. TG synthesis, iodination, storage in follicles, and degradation control thyroid hormone formation and secretion into the circulation. Thyrotropin (TSH), via its receptor (TSHR), increases thyroid hormone levels by up-regulating expression of the sodium iodide symporter (NIS), thyroid peroxidase (TPO), and TG genes. TSH does this by modulating the expression and activity of several thyroid-specific transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, which coordinately regulate NIS, TPO, TG, and the TSHR. Major histocompatibility complex class I gene expression, which also is regulated by TTF-1 and Pax-8 in the thyroid, is decreased simultaneously. This helps maintain self-tolerance in the face of TSH-increased gene products necessary for thyroid hormone formation. In this report we show that follicular TG counter-regulates TSH-increased, thyroid-specific gene transcription by suppressing expression of the TTF-1, TTF-2, and Pax-8 genes. This decreases expression of the TG, TPO, NIS, and TSHR genes, but increases class I expression. TG acts transcriptionally, targeting, for example, a sequence within 1.15 kb of the 5' flanking region of TTF-1. TG does not affect ubiquitous transcription factors regulating TG, TPO, NIS, and/or TSHR gene expression. The inhibitory effect of TG on gene expression is not duplicated by thyroid hormones or iodide and may be mediated by a TG-binding protein on the apical membrane. We hypothesize that TG-initiated, transcriptional regulation of thyroid-restricted genes is a normal, feedback, compensatory mechanism that limits follicular function and contributes to follicular heterogeneity.
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PMID:Autoregulation of thyroid-specific gene transcription by thyroglobulin. 965 73

Of 240 pesticides screened for carcinogenicity by the U.S. Environmental Protection Agency Office of Pesticide Programs, at least 24 (10%) produce thyroid follicular cell tumors in rodents. Thirteen of the thyroid carcinogens also induce liver tumors, mainly in mice, and 9 chemicals produce tumors at other sites. Some mutagenic data are available on all 24 pesticides producing thyroid tumors. Mutagenicity does not seem to be a major determinant in thyroid carcinogenicity, except for possibly acetochlor; evidence is less convincing for ethylene thiourea and etridiazole. Studies on thyroid-pituitary functioning, including indications of thyroid cell growth and/or changes in thyroxine, triiodothyronine, or thyroid-stimulating hormone levels, are available on 19 pesticides. No such antithyroid information is available for etridiazole, N-octyl bicycloheptene dicarboximide, terbutryn, triadimefon, and trifluralin. Of the studied chemicals, only bromacil lacks antithyroid activity under study conditions. Intrathyroidal and extrathyroidal sites of action are found: amitrole, ethylene thiourea, and mancozeb are thyroid peroxidase inhibitors; and acetochlor, clofentezine, fenbuconazole, fipronil, pendimethalin, pentachloronitrobenzene, prodiamine, pyrimethanil, and thiazopyr seem to enhance the hepatic metabolism and excretion of thyroid hormone. Thus, with 12 pesticides that mode of action judgments can be made, 11 disrupt thyroid-pituitary homeostasis only; no chemical is mutagenic only; and acetochlor may have both antithyroid and some mutagenic activity. More information is needed to identify other potential antithyroid modes of thyroid carcinogenic action.
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PMID:Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. 968 70

This is a report of two cases of congenital goiter in which it was possible to indicate, through immunohistochemistry method, the disorder in the hormonal synthesis. One of these cases was of a sixteen-year-old woman, with goiter since childhood who used thyroid hormone replacement for ten years. Pathology showed coloid goiter with follicular adenoma. Immunohistochemistry showed strong mainly apical follicular cell thyroglobulin. Thyroglobulin was not found in the coloid. This finding is compatible with a malfunction of thyroglobulin exocitosis. The reaction for thyroid peroxidase was adequate for the age. The other case was a 13 year-old-boy with goiter and thyroid hormone replacement since the age of 1 year. He presented slight mental and growth retardation. Pathology showed coloid goiter with follicular adenoma. Immunohistochemistry study showed a very weak and diffuse reaction for thyroid peroxidase while the reaction for thyroglobulin was adequate. These findings indicate quantitative defect of thyroid peroxidase.
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PMID:[Immunohistochemical identification of biochemical defect of dyshormonogenetic goiter]. 969 61


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