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PubMed1964

CONTROL OF URACIL SYNTHESIS BY ARGININE IN ESCHERICHIA COLI.

Ben-Ishai, Ruth (Israel Institute of Technology, Haifa), Michal Lahav, and Ada Zamir. Control of uracil synthesis by arginine in Escherichia coli. J. Bacteriol. 87:1436-1442. 1964.-It is shown that arginine affects uracil biosynthesis in Escherichia coli. The effect of arginine on uracil synthesis was analyzed by following the changes in the level of aspartate transcarbamylase, the first specific enzyme in uracil synthesis. In this research, an effect of arginine on aspartate transcarbamylase formation was observed only if the bacteria were preincubated with arginine in the presence of uracil analogues that cause apparent partial derepression of this enzyme. The possible effect of a structural modification of aspartate transcarbamylase by 2-thiouracil, the analogue principally used, is considered. However, it is shown that arginine causes derepression of aspartate transcarbamylase, even if a modification of the enzyme occurs. An effect of uracil on arginine synthesis can also be observed in repressible strains of E. coli, if conditions of partial derepression of the enzymes involved in arginine synthesis prevail. However, neither the derepression of aspartate transcarbamylase by arginine nor the derepression of ornithine transcarbamylase by uracil is accompanied by changes in the level of carbamyl phosphokinase, the enzyme that catalyzes carbamyl phosphate synthesis.

Arginine↗
PubMed2000

Decreased constitutive nitric oxide synthase, but increased inducible nitric oxide synthase and endothelin-1 immunoreactivity in aortic endothelial cells of donryu rats on a cholesterol-enriched diet.

The Donryu rat is resistant to a high cholesterol diet in that typical atheromatous lesions do not develop. Using electron microscopic immunocytochemical techniques, the effects of a CCT diet (4% cholesterol with 1% cholic acid and 0.5% thiouracil) on the distributions of neuronal, macrophage, and endothelial specific nitric oxide synthase (NOS I, NOS II, and NOS III) and endothelin-1 (ET-1) immunoreactivity were examined in the thoracic aortic intima. Atheromatous lesions were absent, but immunocytochemistry showed 1. 4+/-0.52% and 4.0+/-0.9% endothelial cells (EC) with positive staining for NOS I and NOS III, respectively, compared with 16.3+/-2. 5% and 88.6+/-2.48% in control Donryu rats. The CCT-supplemented diet induced expression of NOS II immunoreactivity in thoracic aortic intimal cells. EC, subendothelial macrophages, and smooth muscle cells (SMC) also showed high NOS II-positive staining. The percentage of NOS II-immunoreactive EC was 43+/-1.8%. In control groups, no NOS II immunoreactive cells were observed. The percentage of ET-1 immunopositive cells was also significantly increased by 9. 2+/-0.66% and 64.2+/-1.4% in control and CCT-fed groups, respectively. It is concluded that the administration of a high cholesterol diet in Donryu rats produces endothelial dysfunction associated with changes in the balance of the different isoforms of NOS and ET-1. Therefore, the increase in inducible NOS and ET-1 immunoreactivity seen during the cholesterol-enriched diet appears to be a compensatory reaction of aortic wall cells to the high cholesterol supplementation.

Animals↗
PubMed1996

Application of capillary zone electrophoresis for analysis of thyreostatics.

Capillary zone electrophoresis was optimized for the separation of thiouracil, methylthiouracil and propylthiouracil. Methylthiouracil could be determined in various types of urine (human, bovine, horse), either without any pretreatment or in ethyl acetate extracts, within 15 min. For identification, the simultaneous detection at three UV wavelengths (216, 245 and 278 nm) was advantageously used while for quantification the wavelength of the absorbance maximum at 278 nm was preferred. Under optimized conditions a linear response of the detector in the concentration range 0.1-100 ppm was obtained. On analysis of untreated urine, a detection limit of 0.5 ppm was found; for urine extracts the detection limit was 0.1 ppm. Univocal peak identification, based on absorption at three wavelength, was only possible above 2 ppm. Relative standard deviation for standard solutions of methylthiouracil, diluted in the background electrolyte, was 1%; for methylthiouracil in extracts dissolved in the background electrolyte it was 4.5%, and for methylthiouracil in untreated urine, 12.7%.

Animals↗
PubMed1976

Stimulation of melanotic expression in a melanoma cell line by theophylline.

Theophylline, a phosphodiesterase inhibitor, was found to be a potent stimulator of melanogenesis in the RPMI 3460 hamster melanoma cell line. This stimulation was greater than that caused by either dibutyryl cyclic AMP (db-cAMP) or another phosphodiesterase inhibitor, papaverine. Theophylline and db-cAMP treatments also produced strikingly different morphologies in the monolayered cells. The theophylline effect on melanogenesis was diminished by db-cAMP, whereas simultaneous treatment of cells with db-cAMP and papaverine produced greater stimulation of melanotic activity than either agent acting alone. Theophylline, therefore, may have phenotypic effects that are at least partially independent of phosphodiesterase inhibition. Theophylline stimulated melanin biosynthesis, as measured by rates of 2-[2-14C] thiouracil incorporation, and also caused an increase in the level of tyrosinase (EC 1.10.3.1) activity. This melanotic stimulation was prevented by the presence of cordycepin or cycloheximide. Theophylline inhibited DNA synthesis and mitosis in the melanoma cell cultures but stimulated protein synthesis. However, inhibition of proliferation and the first appearance of induced melanotic activity did not bear an immediate direct relationship to one another.

Catechol Oxidase↗
PubMed1991

The analysis of thiocarbamides by gas chromatography/negative-ion chemical-ionization mass spectrometry.

Thiocarbamides were converted to their di-N-pentafluorobenzyl (PFB) derivatives and analysed by gas chromatography/negative-ion chemical-ionization mass spectrometry with methane as reagent gas. The PFB derivatives of the 2-thiouracils gave mass spectra in which the ion current was carried largely by an ion arising from [M-PFB]-. The derivative was used in the determination of the uptake and metabolism of thiocarbamides by cultures of melanoma cells.

Gas Chromatography-Mass Spectrometry↗
PubMed1977

Myoelectrical and mechanical activity of stomach and intestine in hypothyroid dogs.

Myoelectrical activity was studied in normothyroid and hypothyroid Labrador dogs in the resting state, following injection of pentagastrin, bethanechol chloride, and after feeding. Hypothyroidism was produced by total thyroidectomy and chronic treatment with thiouracil. Electrodes were surgically implanted over the serosa of the stomach, duodenum, jejunum, and ileum and used for repeated recording of myoelectrical activity of gastrointestinal muscles. A strain gauge was implanted over the gastric antrum and served to record mechanical activity of the stomach. As compared with control dogs, hypothyroid animals showed (a) decreased frequency of electrical control activity of the stomach and jejunum, (b) decreased occurrence of electrical response activity (spike potentials) following stimulation, and (c) decreased mechanical response to the same stimulants, ie, pentagastrin, bethanechol chloride, and food.

Animals↗
PubMed1993

Structure-activity relationship of nucleobase ligands of uridine phosphorylase from Toxoplasma gondii.

Seventy-nine nucleobase analogs were evaluated as potential inhibitors of Toxoplasma gondii uridine phosphorylase (UrdPase), and the apparent Ki (appKi) values for these compounds were determined. Based on the inhibition data, a structure-activity relationship for the binding of nucleobase analogs to the enzyme was formulated, using uracil as a reference compound. Two compounds were identified as very potent inhibitors of T. gondii UrdPase, 5-benzyloxybenzylbarbituric acid and 5-benzyloxybenzyluracil, which had appKi values of 0.32 and 2.5 microM, respectively. A comparison of the results from the present study, with similar studies on mammalian UrdPase and thymidine phosphorylase (dThdPase) (Niedzwicki et al., Biochem Pharmacol 32: 399-415, 1993) revealed that there are both similarities and differences between the catalytic site of T. gondii UrdPase and the catalytic sites of the mammalian enzymes with respect to binding of uracil analogs. One compound, 6-benzyl-2-thiouracil, was identified as a potent, specific inhibitor (appKi = 14 microM) of T. gondii UrdPase, relative to mammalian UrdPase and dThdPase.

Animals↗
PubMed1992

Inhibition of lipid deposition in the hypercholesterolemic rat by clentiazem, a calcium channel blocker.

We studied the effects of clentiazem, a calcium channel blocker (1) on the accumulation of lipid in the aorta, (2) on the level of plasma lipids, and (3) on the number of adherent intimal monocytes and foam cells. Seventy Wistar rats were assigned to one of the following groups: (1) regular diet, (2) an atherogenic diet consisting of regular chow with 2% cholesterol, 1% cholic acid, and 0.5% thiouracil (CCT), (3) CCT supplemented with 5 mg/kg/day clentiazem, and (4) CCT with 25 mg/kg/day clentiazem. Animals were sacrificed after 6 or 12 weeks of diet. Aortas were studied by light microscopy after staining with oil red O (ORO) and/or hematoxylin. ORO staining was quantified in both abdominal and thoracic regions of the aorta. The aortas of the clentiazem groups demonstrated significantly less ORO staining than CCT diet controls in thoracic aorta after 6 weeks and abdominal aorta after 12 weeks. There was no significant difference in the plasma lipid concentrations. The clentiazem-treated groups had fewer numbers of adherent monocytes and foam cells. We conclude that clentiazem inhibits lipid deposition in cholesterol-fed rats without lowering plasma lipid concentrations and that the number of intimal monocytes and foam cells is decreased in the presence of this calcium antagonist.

Animals↗
PubMed1989

Corticosteroid receptors in liver cytosol of the clawed toad, Xenopus laevis: influence of thyroid and ovarian hormones.

The glucocorticoid receptor capacity Ro and the dissociation constant Kd were determined in the liver of Xenopus laevis by Scatchard analysis. In 5-year-old female toads Ro was about three times higher than that in males (153.9, 54.3 fmol/mg protein) and Kd was similar in both sexes (4.0, 4.1 nM). Some of the animals used had abnormal enlarged thyroid glands, atrophic ovaries, or both defects in connection with different levels of Ro, but not of Kd, compared to those of normal animals. Females with ovarian atrophy showed significantly lower Ro values, in the same range as in normal males, and a high liver weight. In male and female toads with enlarged thyroid glands and in animals with both defects a significantly higher Ro occurred compared to that of the corresponding group without this abnormality. To study the influence of thyroid hormones on glucocorticoid receptors, young toads (2-3 years old) received injections of 4-phenyl-2-thiouracil, T3, or T4 on 7 consecutive days. Ro and Kd were determined on the following day. Doses of 50 and 500 ng T3 and of 500 and 5000 ng T4 per gram of body weight and day resulted in an increase of Ro up to 250% of the controls. Injections of T3 were more efficient in males than in females. The effect of thyroxine was about the same in both sexes. These observations suggest that thyroid and ovarian hormones exert an influence on glucocorticoid receptor capacity and may belong to the factors which regulate glucocorticoid receptors.

Animals↗
PubMed1977

Hypocholesterolemic action of a novel delta8-dihydroabietamide derivative, THD-341, in rats.

The hypocholesterolemic properties of THD-341, N-(2,6-dimethylphenyl)-delta8-dihydroabietamide, were studied in rats. THD-341 reduced serum cholesterol levels in cholesterol-cholate-fed rats at a concentration of less than 0.001% in the diet or an oral dose of less than 3 mg/kg, once a day. When compared in terms of the 50% inhibitory dose for serum cholesterol elevation (ID 50%, % in diet), THD-341 (0.0008%) was comparable to D-thyroxine (0.0005%), more potent than estradiol (0.003%), and far more potent than clofibrate (0.2%), beta-sitosterol (0.8%), cholestyramine (2%), or nicotinic acid (3%). A daily intravenous injection of THD-341 was also effective (ID 50%: 7 mg/kg). THD-341 reduced serum and liver cholesterol in rats made hypercholesterolemic by 0.3% dietary thiouracil or 0.25% dietary cholate. Liver cholesteriol was more profoundly affected than the serum cholesterol. In normal rats, cholesterol was reduced in liver but not in serum. Its mechanism of action is unknown but the results suggest that THD-341 inhibits cholesterol absorption or re-absorption.

Abietanes↗
PubMed1986

The chemical induction of PR (b) proteins and resistance to TMV infection in tobacco.

Aspirin injected into Xanthi-nc tobacco leaves induces the production of PR protein and resistance to TMV. The concentration of PR protein and resistance increases with increasing aspirin concentration, up to a plateau. 2-Thiouracil and dioxohexahydrotriazine also induce PR protein when injected into tobacco leaves. Barium and manganese salts induced PR protein, but those of eight other cations did not. Certain salts were phytotoxic but did not induce PR protein, confirming that the production of PR protein is not a non-specific stress response.

Aspirin↗
PubMed1983

Chemical modification of cytosine residues of mouse 5 S ribosomal RNA with hydrogen sulfide. (Nucleosides and nucleotides 43).

Cytosine residues of nucleic acids were converted to 4-thiouracil residues with hydrogen sulfide in pyridine and water to examine the secondary and tertiary structures of mouse 5 S rRNA. The cytosine residues at positions 10, 24, 34 (or 36), 39, 44 (or 46) and 63 were converted preferentially when the treatment was carried out at 28 degrees C. This result supports the model of the secondary structure of 5 S rRNA of Nishikawa, K. and Takemura, S. ((1974) FEBS Lett. 40, 106-109) consisting of five helices and five loops. As the temperature was increased to 35 degrees C, additional cytosine residues in positions 26, 52 and 78 were modified to moderate extents.

Animals↗
PubMed2000

Study of heterocycle rings binding to human serum albumin.

The binding of drugs to human serum albumin determines the drug distribution through the systemic circulation and its pharmacological effects on the organism. Then, with the aim of obtaining information concerning the drug structural features which favour their binding on seroalbumin we have studied the seroalbumin binding to the heterocyclic drugs such as warfarin, propylthiouracil and cromoglycate and to similar compounds such as 4-hydroxy-coumarin, 3-acetylcoumarin, coumarin, benzylthiouracil, propyluracil, thiouracil, chromone and chromanol. These compounds were competitively displaced by warfarin at their primary binding sites on seroalbumin. The comparative analysis of the binding data showed that heterocyclic compounds such as benzopyranes (coumarins and chromanol) and benzyl pyrimidines with 4-hydroxyl groups bind specifically in the warfarin binding site. Then, 4-hydroxyl-bencene heterocycles will displace other ligands from the subdomain IIA of the seroalbumin molecule. Therefore, we can predict that the administration concomitant of warfarin, cromoglycate, propylthiouracil and analogous heterocyclic drugs involves the displacement of the drug without 4-hydroxyl and benzyl groups, increasing their free fraction in serum and the amount of active drug.

4-Hydroxycoumarins↗
PubMedDate not supplied

Hypothyroidism increases prolactin secretion and decreases the intromission threshold for induction of pseudopregnancy in adult female rats.

In order to understand the mechanism by which thyroid hormones alter prolactin (PRL) secretion, we investigated the role of tuberoinfundibular dopamine (TIDA) neurons and pituitary and hypothalamus vasoactive intestinal peptide (VIP) in thiouracil- (0. 03% in drinking water for 16 days) induced-hypothyroid adult female rats. The intromission threshold for induction of pseudopregnancy also was examined to evaluate the PRL response to coital stimulation in hypothyroid rats. Hypothyroidism in adult female rats did not affect TIDA neuronal activity as measured by tyrosine hydroxylase activity (DOPA accumulation 30 min after administration of m-hydroxybenzylhydrazine dihydrochloride, 100 mg/kg, i.p.) in the stalk-median eminence compared with that in euthyroid rats, whereas pituitary concentration of VIP was dramatically increased. Plasma concentration of PRL was higher at 1100 h of proestrus and estrus in hypothyroid rats as compared with that of euthyroid rats. The proportion of female rats exhibiting pseudopregnancy was higher in hypothyroid animals (100%) receiving seven intromissions than in euthyroid animals (43%). Administration of L-thyroxine in hypothyroid rats decreased the proportion of pseudopregnancy (40%) to the level of euthyroid animals. These results indicate that the increased level of pituitary VIP probably affects PRL secretion in a paracrine or autocrine manner and account for the hyperprolactinemia induced in hypothyroid female rats. No role for TIDA neurons in PRL elevation can be ascribed. A decrease in the intromission threshold for induction of pseudopregnancy might be due to increased levels of PRL in hypothyroid female rats.

Animals↗
PubMed1992

The pituitary-thyroid axis effects on ocular and orbital tissues: a histological, histochemical, and morphometric study.

This work tests the notion that the effect of thyroid hormone on orbital and ocular tissues is mediated through its action on their lysosomal enzymes. Hyperthyroidism was produced in guinea pigs by thyroxin and TSH; hypothyroidism was induced by thiouracil. After treatment for 10 to 21 days, several ocular and orbital tissues were taken for histological, morphometrical, and histochemical examinations. High acid phosphatase activity was demonstrated in extraocular muscles, optic nerve and the retinal pigment epithelium of thyroxine- and TSH-treated animals. The findings fit the notion that the effects of thyroid hormones are mediated through lysosomes also in ocular and orbital tissues.

Adipose Tissue↗
PubMed1989

Screening and confirmation of thyreostatics in urine by gas chromatography with nitrogen-phosphorus detection and gas chromatography-mass spectrometry after sample clean-up with a mercurated affinity column.

Methods are described for the screening and confirmation of residues of the thyreostatics thiouracil, methylthiouracil and propylthiouracil in urine samples of cattle at levels down to 25 micrograms/l. After a selective preconcentration of the thiol-containing thyreostatics on a mercurated affinity column, the analytes are derivatized by extractive alkylation and analysed by gas chromatography with nitrogen-phosphorus or mass spectrometric detection.

Animals↗