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PubMed2000

Ab initio study on tautomerism of 2-thiouracil in the gas phase and in solution.

Ab initio geometry optimizations were carried out at the HF/3-21G and HF/6-31+G** levels for the six tautomeric forms of 2-thiouracil (2TU, 2TU1, 2TU2, 2TU3, 2TU4, 2TU5) in the gas phase and in solution. To obtain a more definitive estimate of the relative stabilities for 2-thiouracil tautomers in the gas phase, single-point MP2/6-31+G** calculations were performed on the HF/6-31+G** optimized geometries. The tautomeric equilibria in 1,4-dioxane (epsilon = 2.21), acetonitrile (epsilon = 38), and in water (epsilon = 78.54) were studied using the self-consistent reaction field (SCRF) theory. The calculated relative free energies indicated that 2TU is the energetically preferred tautomer in the gas phase and in solution. The stability order of 2-thiouracil tautomers depends on the level of theory and the dielectric constant of the solvent. The obtained results are compared with the available experimental data.

Gases↗

PubMed1997

Effects of consecutive thiouracil exposures in the juvenile and adult single comb White Leghorn chicken on body weight and reproductive performance.

The effects of consecutive exposures to dietary thiouracil (TU) in juvenile and adult Single Comb White Leghorn chickens on plasma thyroxine (T4) concentrations, egg production (EP), egg weight (EW), concentrations eggshell quality were determined. Thiouracil was provided in the feed at levels of 0, 0.1, or 0.2% (PTRT) from 0 to 6 wk of age and at levels of 0 or 0.1% (TRT) from 32 to 38 wk of age. Body weight gain was simulated but T4, EW, EP, and eggshell quality were generally reduced by 0.1% TU TRT. However, TU PTRT alleviated a latent depressing effect of TU TRT on BW after 38 wk of age. Thiouracil PTRT, particularly at the 0.2% level, induced significant decreases in EW but increased EP between 32 and 50 wk. The effects of early thyroid suppression in juveniles with TU PTRT on the subsequent reproduction of adults were primarily in response to a delay in the onset of sexual maturity, and not directly to prolonged responses in T4 or BW that extended into lay.

Aging↗

PubMed1975

The effect of methionine, thiouracil, dienestrol diacetate and thyroprotein on the development and prevention of fatty liver in pullets.

The effect of two levels each of methionine (0.0 and 0.07 percent), thiouracil (0.0 and 0.05 percent), dienestrol diacetate (0.0 and 0.007 percent), and thyroactive casein (0.0 and 0.0125 percent) on the performancy, organ changes, and liver composition in 640 pullets of two strains was studied in a 24 factorial arrangement of treatments. Egg production, egg characteristics, feed conversion, organ weights, and liver composition were parameters measured. Supplemental methionine increased the phosphorus content of liver fat in strain A, but other parameters in the two strains were mot affected by the increase in dietary methionine. The thiouracil increased weight grains, gram of fat per total liver, percent of liver fat, thyroid weight, and heart weight but decreased the phosphorus content of liver fat. Nine typical cases of fatty liver syndrome with large liver hematomas occurred in the thiouracil treated birds and one case occurred in an untreated pullet. Dienestrol diacetate did not affect egg production, egg characteristics, organ weights, and liver composition in the two strains. Thyroprotein decreased weight gain, abdominal fat, liver weight. liver fat, thyroid weight, and percent red cells, but decreased percent blood sports in eggs and adjusted weights of the kidney and heart in both strains.

Adipose Tissue↗

PubMed1991

Effects of selection on plasma thyroxine concentrations in Japanese quail under thiouracil and protein stress.

Three experiments were conducted to measure changes in plasma thyroxine (T4) concentrations occurring in male and female Japanese quail in response to treatment with dietary thiouracil (TU) and different CP levels prior to sexual maturity and to determine the influence of selection for growth under TU and protein stress on this response. Selected and unselected lines of quail were fed diets containing .2% TU or two levels of CP (20 or 28%) or both from 0 to 4 wk of age. Body weight and plasma T4 were measured at 5, 7, and 9 wk of age in Experiments 1 and 2. In Experiment 3, body weight was measured at 2, 4, 5, 7, and 9 wk and T4 at 4, 7, and 9 wk. Thiouracil inhibited growth to a greater degree than did decreased dietary CP. However, offspring from selected quail were more resistant to dietary TU when selection diets contained TU. When fed as part of a selection regimen rather than to unselected birds, low CP, TU diets inhibited body weight increase to a greater degree and longer after birds were returned to control diets. Thyroxine concentrations between 4 and 9 wk were affected by TU but not by CP level. Thiouracil significantly reduced T4 during treatment; however, T4 was elevated by 3 wk after cessation of TU treatment. Increases in T4 were greater and more immediate in selected than in unselected birds. These findings reveal the ability of quail to compensate for thyroid suppression after TU is removed from the diet and the influence of selection on this compensatory response.

Animals↗

PubMed1986

Radio-iodine-labelled 5-iodo-2-thiouracil: a potential radiopharmaceutical for establishing the viability of ocular melanoma after radiation therapy.

Radio-iodine-labelled thiouracil has been evaluated as a radiopharmaceutical for establishing the viability of ocular melanoma after radiation treatment. The uptake of 125I-5-iodo-2-thiouracil (125I-ITU) was studied in X-ray irradiated and non-irradiated melanotic melanomas implanted in Syrian golden hamsters. Uptake of 125I-ITU in melanomas 4 days after irradiation with 40 Gy X-ray was 25% of the value found in non-irradiated controls, 12 days after such treatment it was 10% of that value. Twenty-one days after radiation treatment the melanomas showed regrowth and uptake of 125I-ITU was about equal to that in non-treated controls. Uptake of 125I-ITU in melanomas after 10 Gy X-ray irradiation was higher and uptake in tumours after 20 Gy was only slightly lower than the uptake by non-irradiated melanomas. The results indicate that the iodine labelled-thiouracil uptake test may be useful as an additional diagnostic issue for assessing the viability of ocular melanoma after radiation therapy.

Animals↗

PubMed1979

Structure and tautomerism of the neutral and monoanionic forms of 2-thiouracil, 2,4-dithiouracil, their nucleosides, and some related derivatives.

Ultraviolet and infrared spectrophotometric techniques have been utilized to demonstrate that the monoanionic form of 2-thiouracil in aqueous medium consists of an equilibrium mixture of two tautomeric monoanions, one due to dissociation of the N1 proton, the other to dissociation of the N3 proton, in the approximate ratio 1:1. In contrast to 2,4-diketopyrimidines, and 4-thiouracil, where monoanion formation involves charge delocalization, the two tautomeric monoanions of 2-thiouracil appear to have the charge localized on the O4 position. The neutral forms of 2,4-dithiouracil and 2,4-dithiouridine are in the dithione form in both aqueous and non-aqueous media. The monoanionic form of 2,4-dithiouracil consists of a mixture of two tautomeric monoanions, the predominant one of which is that with the proton on the ring N3, and with charge delocalization on both isomeric monoanions. Such charge delocalization is also present in the monoanion of 2,4-dithiouridine. For the reference compound 2-methylthiopyrimidone-4, the dominant, virtually exclusive, form in chloroform is that with the hydrogen localized on the ring N3, whereas in aqueous medium there is a 1:1 equilibrium mixture of two neutral tautomeric forms, one with the hydrogen on N3, the other with the hydrogen on N1.

Chemical Phenomena↗

PubMedDate not supplied

Hormonal regulation of thermogenesis in goslings. The effects of blockade with thiouracil and propranolol.

Hormonal regulation of thermogenesis in goslings. The effects of blockade with thiouracil and propranolol. Acta Physiol. Pol. 1977, 28 (1): 51-60. The experiments were carried out on 90 male goslings of White Italian breed. In goslings 5 to 7 and 18 to 21-day-old thiouracil (6 mg/100 g i.p., for 3 consecutive days) diminished the cold-induced increase in the metabolic rate. At the end of 1.5 h exposure to 5 degrees C a small but statistically significant drop of body temperature in the thiouracil-treated goslings was noted. Propranolol treatment (2 mg/kg s.c.) had no clear effect neither on body temperature of cold exposed goslings nor on the cold-induced increase in the metabolic rate. The drug caused a significant decrease in the plasma free fatty acid (FFA) levels only in the goslings kept at thermoneutrality. In those exposed to 5 degrees C the plasma FFA levels rose both in the control and propranolol-treated goslings. This suggests that the cold-induced lipolysis in the goslings may be accomplished without mediation of noradrenaline.

Age Factors↗

PubMed1997

Potentiometric and coulometric titration of 6-propyl-2-thiouracil.

A method for the determination of 6-propyl-2-thiouracil involving its reaction with iodine in an alkaline medium is presented. In volumetric titration with potentiometric end-point detection, the range of determination is 125-500 mumol (21-85 mg). In coulometric titration using biamperometric end-point detection, 0.5-5.0 mumol (0.085-0.85 mg) of 6-propyl-2-thiouracil was successfully determined. The RSD in all applied techniques was < 1%. The methods developed were applied to the determination of 6-propyl-2-thiouracil in tablets.

Antithyroid Agents↗

PubMed2006

Unambiguous identification of thiouracil residue in urine collected in non-treated bovine by tandem and high-resolution mass spectrometry.

Thyrostats are banned compounds in Europe since 1981 (directive 81/602/EC) because of their carcinogenic and teratogenic properties. However, the occurrence of thiouracil (TU) in bovine urines from national monitoring plans with quantifications in the range 1-10 microg . L(-1) occasionally raises the question of its origin which might either be the consequence of an illegal administration or the result of 'endogenous' production. In order to definitively and unambiguously identify the so-called thiouracil signal in non-treated bovine urines, independent mass spectrometry (MS) approaches have been used. Different reagents (3-IBBr, 3-BrBBr and PFBBr) were used to derivatise and to extract TU from urine samples and characterisation of the residues was performed by means of different MS approaches [LC/(ESI-)MS/MS, GC/(EI+)MS/MS and HRMS (EI and NCI)]. These combined strategies allowed for an independent and confident identification of TU in bovine urine samples collected from animals never treated with any thyrostatic drugs. This result is of prime importance for laboratories and risk managers involved in the field of forbidden growth promoters control: detection of TU residue in bovine urine will have to be carefully considered as a non-systematic proof of illegal administration.

Agriculture↗

PubMed1988

Thiouracil and antibody titers of chickens from lines divergently selected for antibody response to sheep erythrocytes.

Chickens from lines selected for high (HA) and low (LA) antibody response to sheep red blood cells (SRBC) were fed ad libitum either a diet containing 0 (control) or .1% thiouracil (TF) throughout two trials. Chicks were injected intravenously with .1 ml of .25% SRBC at 37 days of age in Trial 1, and a booster of the same dosage was given to half of these chicks at 61 days of age. Antibody titers were measured 5 and 3 days after primary and secondary inoculations. In Trial 2, primary inoculations of SRBC were given at 21 and 38 days of age, and chicks were bled 3, 5, 7 and 10 days after inoculation. TF chicks had lower body weights and higher feed efficiencies than controls. Plasma thyroxine (T4) concentrations were similar for both lines, but line by diet interactions were present for plasma triiodothyronine (T3) and T3/T4 ratios. When fed the control diet, T3 concentrations and T3/T4 ratios were higher for line HA than line LA, but the pattern was reversed when thiouracil was fed. Antibody titers to SRBC in both trials were higher for HA than LA chicks, but were similar for TF and control chicks. Persistence of elevated titers appeared to be greater in TF than control chicks. There were no differences between TF and control chicks for heterohphil/lymphocyte ratios.

Animals↗

PubMed1994

Specific incorporation of 2-thiouracil into biological melanins.

2-Thiouracil (TU), an antithyroid drug, is generally recognized as a highly specific melanoma seeker owing to its capability of being selectively accumulated into active melanin-producing tissues. We recently reported evidence that in vitro TU is capable of reacting with dopaquinone (DQ), an early intermediate in melanin biosynthesis, to give an addition product characterized as 6-S-thiouracildopa (TD). However, several aspects of the mechanism of the uptake of TU into melanin in vivo still need to be clarified. We report here the extremely rapid incorporation of [2-14C]thiouracil into melanoma tumors growing subcutaneously in mice and show its selective accumulation into melanin by isolation and purification of the pigment fraction. Formation of the TD adduct in the tumor was examined by HPLC analysis of the soluble fractions of the tissue homogenates: however, no trace of TD could be detected on account of its rapid oxidation by the melanogenic enzyme tyrosinase, as evidenced by in vitro kinetic measurements. Monitoring the course of the tyrosinase-catalyzed oxidation of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) in the presence of TU, at various molar ratios, provided evidence for the ability of the drug to affect melanogenesis by interaction with biosynthetic intermediates beyond the DQ stage, suggesting other possible modes for its chemical binding to the growing pigment.

Animals↗

PubMed1989

Direct electrophilic iodination of 2-thiouracil using Iodo-Gen.

5-Iodo-2-thiouracil (ITU) is of interest due to its ability to bind specifically to the pigment melanin during melanogenesis and is of potential value in the diagnosis and treatment of malignant melanoma. Radioiodinated ITU was prepared directly from 2-thiouracil in a two-phase reaction using Iodo-Gen in 0.05 M phosphate buffer pH 7.0. The identity radiochemical purity and stability of the product were checked by reversed-phase high pressure liquid chromatography (HPLC). ITU labeled with 123I, 125I or 131I has been produced in millicurie amounts and isolated on a semi-preparative reversed-phase HPLC column. Production time was 2-3 h, overall radiochemical yields averaged 80%; the radiochemical purity was greater than 98%. Specific activities on the order of 20 Ci/mmol have been obtained.

Animals↗

PubMed2005

Electrochemical oxidation of 2-thiouracil at pyrolytic graphite electrode.

2-Thiouracil has been studied in phosphate buffers of pH 1.95-11.08 using linear and cyclic sweep voltammetry, coulometry, controlled potential electrolysis and spectral studies. One well-defined oxidation peak I(a) in the pH range 1.95-11.08 was noticed. The number of electrons involved in peak I(a) was found to be four in a thin layer cell whereas under exhaustive electrolysis condition oxidation was found to involve six electrons. A reduction peak II(c) (2e, 2H(+)) is noticed in the reverse sweep. Spectral studies during oxidation were carried out at different pH. Kinetic studies indicated that the decay of the UV-absorbing intermediate is a first order reaction. The products of the electrooxidation have been characterized and a tentative EC mechanism has been suggested for the oxidation of 2-thiouracil.

Electrochemistry↗

PubMed2006

Spectral properties of some metal complexes derived from uracil-thiouracil and citrazinic acid compounds.

The reaction of FeCl(3) with uracil (H(2)L(1)), citrazinic acid (H(2)L(6)), 5-(phenylazo)citrazinic acid (H(2)L(7)), 5-(m-hydroxyphenylazo)citrazinic acid (H(2)L(8)) and 5-(m-nitrophenylazo)citrazinic acid (H(2)L(9)) leads to the formation of complexes with the empirical formula Fe(HL)(3).nH(2)O (n=1-3). All of the prepared complexes have octahedral complexation geometry where the azo group is not the reactive site for complexation. Thiouracil (H(2)L(2)) and the 5-(substituted phenylazo)thiouracil (H(2)L(3)-H(2)L(5)) ligands are bidentates on complexation with Co(II), Ni(II) and Cu(II). The complexes have been characterized by elemental analyses, IR, electronic spectra, magnetic susceptibility, DTA, electron spin resonance (copper complexes) and Mössbauer spectra (iron complexes). The coordination bond lengths between the metal ion and the active centers for complexation were calculated.

Acids↗

PubMed1978

Thiouracil-induced myocardial fibrosis.

Rabbits were fed with thiouracil for 8 months. Subsequently their hearts were examined electron microscopically as well as biochemically for collagen and hexosamine content. Chronic treatment with thiouracil induced an increase in interstitial connective tissue collagen and hexosamine without visible necrosis. As seen by electron microscopy, the increase in collagen content might have been caused by stimulation of the fibrocytes. Furthermore, the heart muscle cells showed deep indentations and bulges of the cell membrane and an enlargement of the T-system.

Animals↗

PubMed2003

Vibrational frequencies and structure of 2-thiouracil by Hartree-Fock, post-Hartree-Fock and density functional methods.

Vibrational study of the biomolecule 2-thiouracil was carried out. Ab initio and density functional calculations were performed to assign the experimental spectra. A comparison with the uracil molecule was made, and specific scale factors were deduced and employed in the predicted frequencies of 2-thiouracil. Several scaling procedures were used. The geometry structure of the molecule was determined. The effect of sulfur substitution at C2 position in the uracil molecule, on the N1-H and N3-H frequencies and intensities reflects changes in proton donor abilities of these groups. Calculations with the 6-31 G** basis set with HF and DFT methods appear in general to be useful for interpretation of the general features of the IR and Raman spectra of the molecule. Using specific scale factors a very small error was obtained. The use of these specific scale factors resolve and correct some of the controversial assignments in the literature.

Spectrophotometry, Infrared↗

PubMed1991

Boron-containing thiouracil derivatives for neutron-capture therapy of melanoma.

Boron-containing derivatives of 2-thiouracil and 2,4-dithiouracil and the corresponding 6-propyl compounds, containing a dihydroxyboryl group in the 5-position, have been prepared. These compounds accumulate in B16 melanoma in mice in concentrations up to 30 micrograms of boron per gram tissue. The uptake persists. The toxicity of both 2-thiouracil derivatives is low. These compounds are therefore good candidates for boron neutron-capture therapy of malignant melanoma.

Animals↗

PubMed1996

Mechanism of selective incorporation of the melanoma seeker 2-thiouracil into growing melanin.

The mechanism of selective incorporation of 2-thiouracil (TU), a highly specific melanoma seeker, into growing melanins was investigated both in vitro and in vivo. Methods used included direct analysis of the melanins, by evaluation of the absorption at 350 nm (A350) and chemical degradation coupled with HPLC quantitation of pigment makers, i.e., pyrrole-2,3-dicarboxylic acid (PDCA) and pyrrole-2,3,5-tricarboxylic acid (PTCA), as well as biosynthetic experiments involving tyrosinase-catalyzed oxidation of DOPA, 5,6-dihydroxyindole (DHI), and 5,6-dihydroxyindole-2-carboxylic acid (DHICA). Injection of radiolabeled TU into melanoma-bearing mice resulted in a rapid incorporation of the drug into the tumor pigment, with a substantial decrease in A350 and in PTCA yields. Similar changes in the absorption properties were observed in biosynthetic melanins prepared in the presence of TU, whereas the yields of PTCA and PDCA varied depending on the pigment precursor used. When incubated with DOPA in the presence of tyrosinase, TU profoundly modified the normal course of melanogenesis, favoring formation of a complex mixture of addition products consisting mainly of 6-S-thiouracil-DOPA as well as DHI-TU adducts. The latter were obtained in larger amounts by enzymatic oxidation of DHI in the presence of TU and were identified as the 3- and 2-substituted adducts 1 and 2, the dimer 3, and the trimer 4. Similar reactions carried out on DHICA yielded the 4-substituted adduct 5, the dimer 6, and the trimer 7. A new mechanistic scheme for the incorporation of TU into growing melanin is proposed, which envisages nucleophilic attack of the thioureylene moiety of TU to transient quinonoid intermediates in the melanin pathway, chiefly dopaquinone and 5,6-indolequinones, followed by entrainment of the resulting adducts into the growing pigment via oxidative copolymerization with DHICA and/or DHI.

Animals↗