Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The conversion of T4 to T3 in the brain and anterior pituitary gland contributes significantly to the T3 content of these tissues and appears to be an important modulator of thyroid hormone action. In the present study, the antimanic agent lithium was demonstrated in cultured neural and pituitary tissue to have a significant inhibitory effect on the activity of low Km (type II) iodothyronine 5'-deiodinase (I5'D), the enzyme mediating T3 formation. At medium lithium concentrations of 3.3-5 mM, 15'D activity was decreased 44 +/- 3% (P less than 0.001) in the NB41A3 mouse neuroblastoma cell line and 48 +/- 2% (P less than 0.001) in the GH3 rat pituitary tumor cell line. This inhibitory effect was only observed in intact cells. Significant inhibition of this enzymatic process was also noted in the anterior pituitary gland of thyroidectomized rats injected 3-24 h earlier with either 4 or 10 mmol/kg BW LiCl. This decrease in low Km I5'D activity was accompanied by significant decreases in the serum T3 concentration and the pituitary nuclear T3 content. Renal high Km (type I) I5'D activity was unaffected by lithium administration. These studies demonstrate that lithium, an agent of proven therapeutic benefit in patients with manic-depressive illness, can affect changes in T4 metabolism and cellular T3 content in neural and anterior pituitary tissue. Given the prominent mood changes that occur in patients with disordered thyroid function, this finding suggests that the therapeutic benefits of lithium in affective illness may be derived in part from alterations in thyroid hormone economy in the brain.
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PMID:Regulatory effect of lithium on thyroxine metabolism in murine neural and anterior pituitary tissue. 303 Jul

The central nervous system manifests complex homeostatic mechanisms for the maintenance of thyroid hormone economy. The present studies used the NB41A3 mouse neuroblastoma cell line as a model system to study the hormonal regulation of the enzymatic conversion of T4 to T3 in neural tissue. NB41A3 cells manifested a thiol-dependent 6-n-propyl-2-thiouracil-insensitive iodothyronine 5'-deiodinase (I5'D) with a Km for T4 of approximately 10 nM. I5'D activity was increased 2- to 4-fold in cells grown in thyroid hormone-depleted medium. Exposure of cells in situ to various thyroid hormones resulted in a rapid dose-dependent inhibition of enzyme activity with the following order of potency: rT3 = T4 greater than T3. The potent inhibitory effect of rT3 on I5'D activity could not be attributed to substrate competition with T4 in the reaction assay. The addition of dexamethasone (2 X 10(-7) M) to the culture medium also inhibited I5'D activity by 46 +/- 6% (+/- SE; n = 4 experiments; P less than 0.02), whereas insulin and epinephrine were without effect. In other experiments, saturation analysis using a purified preparation of isolated nuclei from NB41A3 cells demonstrated the presence of saturable, high affinity nuclear binding sites which had a Kd value for T3 of 0.13 +/- 0.05 nM and a maximum binding capacity of 0.13 +/- 0.01 pmol T3/mg DNA. These studies demonstrate that NB41A3 cells have a low Km (type II) I5'D process and nuclear T3-binding sites very similar to those previously described in the rat central nervous system. I5'D activity in this cell line appears to be regulated by multiple serum factors, including thyroid hormones and glucocorticoids. The potent regulatory effect of rT3 and T4 suggests that T3 formation by thyroid hormones in neural tissue is controlled by a unique cellular mechanism independent of the nuclear T3 receptor. Since tissue and plasma concentrations of T4 are considerably higher than those of rT3, the former hormone is likely to be the principal thyroid hormone regulating this enzymatic process.
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PMID:Hormonal control of a low Km (type II) iodothyronine 5'-deiodinase in cultured NB41A3 mouse neuroblastoma cells. 352 24

Methylmercury (MeHg) is a well-known neurotoxicant and prenatal exposure to MeHg results in severe brain damage. Since MeHg has a high affinity for thiol groups, we sought to determine whether MeHg inhibited type II iodothyronine deiodinase (D2) activity, by which prohormone thyroxine (T4) is converted to active thyroid hormone, 3,5,3'-triiodothyronine (T3) in the brain, using NB41A3 mouse neuroblastoma cells. In MeHg-treated cells, D2 activity was inhibited in a dose- and time-dependent manner; relatively low concentrations of MeHg (30 nM) inhibited D2. Kinetic analysis using a double reciplocal plot of D2 activity revealed competitive inhibition by MeHg. DTT protected D2 from MeHg when cells were incubated with both MeHg and DTT or when MeHg was added to the assay buffer containing DTT and cell sonicates from untreated cells. Removal of MeHg from culture medium did not recover D2 activity. These results demonstrate that MeHg inhibited D2 activity in NB41A3 cells and the selenocysteine in the catalytic subunit of D2 may be involved in the inhibitory action of MeHg. Further our results suggest that T3 deficiency due to D2 inhibition in the brain may be involved in the neurotoxicity of MeHg.
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PMID:Methylmercury inhibits type II 5'-deiodinase activity in NB41A3 neuroblastoma cells. 1614 Apr 79

Type I iodothyronine deiodinase (D1) and type II iodothyronine deiodinase (D2) catalyze the activation of the prohormone T4 to the active hormone T3; type III iodothyronine deiodinase (D3) catalyzes the inactivation of T4 and T3. D3 is highly expressed in brain, placenta, pregnant uterus, and fetal tissues and plays an important role in regulating thyroid hormone bioavailability during fetal development. We examined the activity of the different deiodinases in human cell lines and investigated the regulation of D3 activity and mRNA expression in these cell lines, as well as its possible coexpression with neighboring genes Dlk1 and Dio3os, which may also be especially important during development. D1 activity and mRNA were only found in HepG2 hepatocarcinoma cells, and D2 activity was observed in none of the cell lines. D3 activity and mRNA was found in ECC-1 endometrium carcinoma cells, MCF-7 mammacarcinoma cells, WRL-68 embryonic liver cells, and SH-SY5Y neuroblastoma cells, but not in the HepG2 hepatocarcinoma cell line or in any choriocarcinoma or astrocytoma cell line. We demonstrated that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate increased D3 activity 2- to 9-fold in ECC-1, MCF-7, WRL-68, and SH-SY5Y cells. Estradiol increased D3 activity 3-fold in ECC-1, but not in any other cells. Dexamethasone decreased D3 activity in WRL-68 cells only in the absence of fetal calf serum. Incubation with retinoids increased D3 activity 2- to 3-fold in ECC-1, WRL-68, and MCF-7 cells but decreased D3 activity in SH-SY5Y cells. D3 expression in the different cells was not affected by cAMP or thyroid hormone. Interestingly, D3 mRNA expression in the different cell lines strongly correlated with Dio3os mRNA expression and in a large set of neuroblastoma cell lines also with Dlk1 expression. In conclusion, we identified different human D3-expressing cell lines, in which the regulation of D3 expression is cell type-specific. Our data suggest that estradiol may be one of the factors contributing to the induction of D3 activity in the pregnant uterus and that in addition to gene-specific regulatory elements, more distant common regulatory elements also may be involved in the regulation of D3 expression.
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PMID:Regulation of type III iodothyronine deiodinase expression in human cell lines. 1693 42

We have recently reported that methylmercury (MeHg) inhibits type II iodothyronine 5'-deiodinase (D2) activity in mouse neuroblastoma NB41A3 cells. In the present study, we determined the biological significance of D2 inhibition by MeHg. GH3 rat pituitary tumor cells were treated with MeHg and D2 activity and production of a thyroid hormone-responsive gene product, growth hormone (GH) were analyzed. MeHg inhibited D2 activity and decreased thyroxine (T4)-induced, but not 3,3',5-triiodothyronine (T3)-induced GH secretion in GH3 cells. Our results suggest that MeHg inhibition of D2 activity might be involved in the inhibition of GH production in GH3 cells. Thus, D2 inhibition could be a novel mechanism involved in MeHg toxicity.
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PMID:Methylmercury inhibition of type II 5'-deiodinase activity resulting in a decrease in growth hormone production in GH3 cells. 1758 71