UNIPROT:Q8NEX9 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 37-yr-old woman with nontoxic goiter is presented. The thyroid 131I uptake at 3 and 24 hr were, respectively, 77.1% and 81.4% dose. Thiocyanate discharged 65.5% of the accumulated 131I in 30 min. In vitro organification of iodine in the thyroid homogenate from the patient was impaired and it was restored to normal by the addition of H2O2, glucose, and glucose oxidase system, FAD, or reduced cytochrome b5. Riboflavin, FMN, oxidized cytochrome b5, oxidized or reduced cytochrome c, NAD(H), and NADP(H) were ineffective in the reaction. The microsomal NADH-cytochrome b5 reductase activity was definitely low in the patient's thyroid. It was augmented to a normal level by incubation of the microsomes with FAD for 30 min or more. The activities of thyroid peroxidase, G6-PD, 6-PGD, catalase, protease, and NADPH-cytochrome c reductase were within normal limits. The major thyroid protein was normal thyroglobulin which could be readily iodinated in the presence of H2O2 and horse radish peroxidase. These findings suggest the correlation of an iodide organification defect with a cytochrome b5 reductase deficiency. Administration of high doses of FAD led to the restoration of thyroidal iodide organification mechanism associated with an increased thyroid hormone production and to a marked decrease of the goiter. Riboflavin was given without effect even at a high dosage level. Consequently, it seems likely that the deficient cytochrome b5 reductase activity in this patient is due to a defect in the biosynthesis of FAD, the coenzyme of the reductase, from riboflavin.
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PMID:Deficient cytochrome b5 reductase activity in nontoxic goiter with iodide organification defect. 116 26

The role of thyroid hormone in regulating the expression of the flavoprotein NADPH cytochrome P450 reductase was studied in adult rats. Depletion of circulating thyroid hormone by hypophysectomy, or more selectively, by treatment with the anti-thyroid drug methimazole led to a 75-85% depletion of hepatic microsomal P450 reductase activity and protein in both male and female rats. Thyroxine substantially restored P450 reductase activity at a dose that rendered the thyroid-depleted rats euthyroid. Microsomal P450 reductase activity in several extrahepatic tissues was also dependent on thyroid hormone, but to a lesser extent than in liver (30-50% decrease in kidney, adrenal, lung, and heart but not in testis from hypothyroid rats). Hepatic P450 reductase mRNA levels were also decreased in the hypothyroid state, indicating that the loss of P450 reductase activity is not a consequence of the associated decreased availability of the FMN and FAD cofactors of P450 reductase. Parallel analysis of S14 mRNA, which has been studied extensively as a model thyroid-regulated liver gene product, indicated that P450 reductase and S14 mRNA respond similarly to these changes in thyroid state. In contrast, while the expression of S14 and several other thyroid hormone-dependent hepatic mRNAs is stimulated by feeding a high carbohydrate, fat-free diet, hepatic P450 reductase expression was not increased by this lipogenic diet. Injection of hypothyroid rats with T3 at a supraphysiologic, receptor-saturating dose stimulated a major induction of hepatic P450 reductase mRNA that was detectable 4 h after the T3 injection, and peaked at approximately 650% of euthyroid levels by 12 h. However, this same treatment stimulated a biphasic increase in P450 reductase protein and activity that required 3 days to reach normal euthyroid levels. T3 treatment of euthyroid rats also stimulated a major induction of P450 reductase mRNA that was maximal (12-fold increase) by 12 h, but in this case no major increase in P450 reductase protein or activity was detectable over a 3-day period. Together, these studies establish that thyroid hormone regulates P450 reductase expression by pretranslational mechanisms. They also suggest that other regulatory mechanisms, which may involve changes in P450 reductase protein stability and/or changes in the translational efficiency of its mRNA, are likely to occur.
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PMID:Thyroid hormone stimulation of NADPH P450 reductase expression in liver and extrahepatic tissues. Regulation by multiple mechanisms. 173 85

The sexually differentiated microsomal enzyme steroid 5 alpha-reductase (NADPH: delta 4-3-oxosteroid 5 alpha-oxido-reductase, EC 1.3.99.5) catalyzes the NADPH-dependent conversion of testosterone to 5 alpha-dihydrotestosterone, a more potent androgen. In rat liver, this enzyme is expressed at a 10-fold higher level in adult females as compared to adult males. The pituitary regulation of this enzyme and its mRNA was studied in untreated and hypophysectomized rats and in rats rendered hypothyroid by treatment with the antithyroid drug methimazole. Hepatic 5 alpha-reductase activity was elevated 8-fold, to 85% of adult female levels, in adult male rats given growth hormone by continuous infusion. This same treatment was only partially effective in restoring 5 alpha-reductase in rats depleted of endogenous growth hormone by hypophysectomy, indicating that other pituitary-dependent factors contribute to the elevation observed in the inact animals. Further analysis revealed that thyroxine, but not adrenocorticotropic hormone (ACTH) or chorionic gonadotropin, could elevate 5 alpha-reductase activity and mRNA when given to the hypophysectomized rats and that this effect was enhanced by the presence of growth hormone. This thyroid hormone dependence was confirmed by the decrease in hepatic 5 alpha-reductase expression in hypothyroid rats and by its substantial restoration following thyroxine replacement. Thyroxine also stimulated expression of another female-predominant hepatic mRNA, encoding the steroid 16 alpha-hydroxylase cytochrome P-450f (IIC7), in a manner that was independent of the stimulatory effect of growth hormone on this transcript. In contrast, thyroid hormone did not significantly affect protein or mRNA levels of the growth hormone-stimulated, female-specific steroid sulfate 15 beta-hydroxylase P-450 2d (IIC12). These findings establish that thyroid hormones act at a pretranslational level to modulate the expression of some, but not all, growth hormone-stimulated hepatic mRNAs and demonstrate that both thyroxine and growth hormone can independently contribute to the sex-dependent expression of hepatic enzymes of steroid metabolism.
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PMID:Pretranslational control by thyroid hormone of rat liver steroid 5 alpha-reductase and comparison to the thyroid dependence of two growth hormone-regulated CYP2C mRNAs. 217 47

Hyperglycemia and impaired glucose tolerance are frequently observed in patients with hyperthyroidism. However, little is known about whether altered polyol metabolism in hyperthyroidism is present or not. To examine changes in polyol metabolism in hyperthyroidism, we investigated changes in erythrocyte sorbitol, glyceraldehyde reductase (GAR) and sorbitol dehydrogenase (SDH) activities during hyperthyroid and euthyroid states in patients with thyrotoxicosis. Mean levels of erythrocyte sorbitol and GAR were 32.0 +/- 1.6nM/g.Hb and 147.1 +/- 0.3mU/g.Hb, respectively. In thyrotoxic patients in a hyperthyroid state, these values were significantly higher than those in euthyroid controls. Mean level of erythrocyte SDH in thyrotoxic patients was weak but was significantly increased in comparison with that of euthyroid controls. However, mean levels of erythrocyte sorbitol and GAR were remarkably reduced to 23.6 +/- 1.4nM/g.Hb and 125.3 +/- 4.6mU/g.Hb in thyrotoxic patients in a euthyroid state after treatment with anti-thyroid drugs or by subtotal thyroidectomy. Mean level of SDH, on the other hand, was increased after the treatment. In addition, positive correlations were observed between the level of erythrocyte sorbitol or GAR, and the level of free thyroxine(FT4) or free triiodothyronine(FT3). A negative correlation was observed between the level of erythrocyte SDH and the level of FT4 or FT3. These results suggest that the level of erythrocyte sorbitol may be increased through direct acceleration of erythrocyte GAR activity by increased thyroid hormone levels in patients with thyrotoxicosis.
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PMID:[Erythrocyte sorbitol levels in patients with thyrotoxicosis]. 228 82

The effects of treatment with adrenoceptor blockers on sites regulating lipid metabolism were studied in golden hamsters. In hamsters fed a standard chow, doxazosin, propranolol, and atenolol did not affect plasma cholesterol or triglycerides. After hypercholesterolemia was induced by feeding a cholesterol-enriched diet, doxazosin lowered plasma cholesterol by 12%. Lipoprotein lipase activity in adipose tissue and in the heart was not changed by any of the treatments. Hepatic lipase activity in the liver and blood was lowered by 31% in the doxazosin-treated animals. Hepatic cholesterol synthesis, measured as acetate incorporation into cholesterol and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase activity, was also lowered in the doxazosin-treated hamsters. After norepinephrine administration to cholesterol-fed hamsters, atenolol increased (+8%) and doxazosin decreased (-35%) plasma triglycerides. Plasma cholesterol levels and hepatic cholesterol synthesis were no longer significantly affected by doxazosin. In norepinephrine-treated animals, adipose tissue lipoprotein lipase activity was enhanced (+30%) by doxazosin. Hepatic lipase activity in plasma and liver, which was lowered by norepinephrine, was increased by doxazosin. In hamsters not treated with norepinephrine, adrenoceptor blockers had no effect on plasma insulin or thyroid hormone, but with norepinephrine, levels of both insulin and thyroid hormone were increased by doxazosin. These data indicate that selective alpha 1-inhibition with doxazosin may interfere with lipid metabolism at several regulatory sites. The effects depend to a large extent on nutritional and hormonal status. Doxazosin might exert these effects partly via influences on other hormones.
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PMID:Effects of doxazosin on lipids, lipoprotein lipases, and cholesterol synthesis in the golden hamster. 247 Oct 16

In an effort to define the mechanism by which thyroid hormone increases the synthesis of hepatic cholesterol, we have investigated both in hypophysectomized and methimazole-treated hypothyroid rats the time course of T3 effects on plasma cholesterol concentration, total hepatic cholesterol, the rate of biliary secretion of cholesterol, bile acids, and phospholipids, and the activity and mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, the rate-limiting enzyme in the hepatic synthesis of cholesterol. A single dose of 200 micrograms T3 was estimated to maintain at least 90% nuclear occupancy for the ensuing 54 h of the experiment. In both preparations the relative rise in biliary secretion of cholesterol exceeded that of other biliary constituents and preceded by 12 h an increase in HMG-CoA reductase enzyme activity and its mRNA. The level of total hepatic cholesterol remained constant throughout the experiment. We interpret these findings to suggest that T3-stimulated cholesterol synthesis is mediated by an antecedent T3-induced rise in biliary cholesterol secretion. We postulate that biliary cholesterol secretion is augmented by an intrahepatic shift of cholesterol and depletion of the hepatic sampling center responsible for the feedback regulation of cholesterol synthesis. The level of HMG CoA reductase mRNA appeared to govern enzyme activity in both preparations, but the ratio of mRNA to hepatic enzyme activity was substantially greater in the methimazole-treated compared with the hyphophysectomized animals.
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PMID:Time course of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and messenger ribonucleic acid, biliary lipid secretion, and hepatic cholesterol content in methimazole-treated hypothyroid and hypophysectomized rats after triiodothyronine administration: possible linkage of cholesterol synthesis to biliary secretion. 273 58

Administration of dexamethasone to hypophysectomized rats treated with thyroid hormones blocked the increase in hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA and enzyme activity which occurred in response to thyroid hormone treatment. The rate of transcription of the rat liver HMG-CoA reductase gene measured by "run-on" assays in isolated nuclei was not diminished by dexamethasone. The half-life of HMG-CoA reductase mRNA was decreased from 12-15 to 2-3 h by dexamethasone treatment of hypophysectomized rats fed thyroid powder. Adrenalectomy caused the half-life of HMG-CoA reductase mRNA to increase from 3 to 10 h, suggesting that endogenous glucocorticoids also regulate reductase mRNA stability. Reductase mRNA levels were increased only 5-fold in thyroidectomized rats fed thyroid powder compared to a 20- to 40-fold increase in similarly treated hypophysectomized rats. In thyroidectomized rats, reductase mRNA had a half-life of only 1.5 h. Thyroid hormone treatment increased this to 4.5 h, significantly less than that of similarly treated hypophysectomized rats. Hydrocortisone, like dexamethasone, lowered reductase mRNA levels, but the biologically inactive analogue epihydrocortisone did not affect reductase mRNA or activity. These results suggest that glucocorticoids decrease the abundance of HMG-CoA reductase mRNA by stimulating its degradation.
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PMID:Post-transcriptional regulation of 3-hydroxy-3-methylglutaryl-CoA reductase mRNA in rat liver. Glucocorticoids block the stabilization caused by thyroid hormones. 290 40

The effects of thyroid hormone on the NADH-tetrazolium reductase activity (oxidative metabolism marker) of soleus (slow-oxidative) and tensor fascia lata (fast-glycolytic) motoneurons were determined and compared with changes in a variety of enzyme activities in the corresponding muscle fibers. Histochemical assays have demonstrated a selective and qualitative conversion in muscle fiber ATPase and quantitative increases of NADH-tetrazolium reductase (oxidative) and mitochondrial alpha-glycerophosphate dehydrogenase (glycolytic) activities in the soleus muscle. Paralleling the selective action upon the soleus slow muscle fibers was a selective central nervous system effect of thyroid hormone on oxidative enzymes of soleus slow-oxidative motoneurons. This indicates that either thyroid hormones act directly and specifically on slow motoneurons or that conversion of the muscle fibers by thyroid hormones produces secondary changes in the motoneuron. These data strengthen the hypothesis that oxidative enzyme activities in motoneurons are tightly matched with oxidative enzyme activities in muscle fibers.
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PMID:Hyperthyroidism selectively increases oxidative metabolism of slow-oxidative motor units. 295 23

The mechanisms by which thyroid hormones increase hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase mRNA levels were investigated in hypophysectomized rats. Feeding these rats a diet supplemented with 0.5% desiccated porcine thyroid powder resulted in a 5-fold increase in the rate of transcription of the HMG-CoA reductase gene as measured by in vitro "run-on" transcription assays in isolated rat liver nuclei. Time courses of change in reductase mRNA, showing the kinetics of approach to new steady-state levels, indicate that reductase mRNA is also 4-6-fold more stable in thyroid hormone-treated animals than in non-treated animals. Reductase mRNA decayed with a half-life of 2.5 h when mevinolin, a potent inhibitor of HMG-CoA reductase, and colestipol, a bile acid sequesterant, were removed from the diet of hypophysectomized rats. When these drugs were removed from the diet of thyroid hormone-treated hypophysectomized rats, reductase mRNA decayed with a half-life of 15 h. Treating rats with only mevinolin and colestipol increased reductase mRNA levels without stabilizing the mRNA. Administration of cycloheximide to thyroid hormone treated rats rapidly decreased HMG-CoA reductase mRNA levels by destabilizing reductase mRNA and decreasing reductase gene transcription. Cycloheximide treatment had no effect on beta-actin gene transcription or steady state levels of beta-actin mRNA. These results suggest that a short-lived protein(s) may mediate the transcriptional and post-transcriptional effects of thyroid hormones on HMG-CoA reductase mRNA levels.
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PMID:Transcriptional and posttranscriptional regulation of rat hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase by thyroid hormones. 341 Aug 47

The effect of environmental temperature on the content of cytochrome P-450 or the activity of nicotinamide adenine dinucleotide phosphate-cytochrome c (NADPH-cytochrome c) reductase was examined by using microsomes prepared from rats kept at 30 degrees C or 15 degrees C for 14 d. The warm exposure (30 degrees C for 14 d) resulted in a significant reduction of the activity of NADPH-cytochrome c reductase though the content of cytochrome P-450 was not changed. The level of thyroxine and 3,3',5-triiodothyronine was reduced by the warm exposure. From the present observation, it was suggested that the effect of environmental temperature on the metabolism of drugs was due to the activity of NADPH-cytochrome c reductase mediated by the level of thyroid hormone.
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PMID:Effect of environmental temperature on the content of cytochrome P-450 and activity of NADPH-cytochrome C reductase in rats. 642 88

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