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PubMed1976

Interrelationships between athyreotic and manganese-deficient states in rats.

Possible interrelationships of manganese-deficient and hypothyroid (thiouracil treatment) states in rats were examined. Clinical signs, necropsy changes, and plasma thyroxine concentrations were determined in control rats (group A), thiouracil-treated (hypothyroid) rats (group B), rats given manganese-deficient feed (group C), and rats given thiouracil and manganese-deficient feed (group D). Clinical signs observed included a hyperemic condition of the ears in group C and D rats that was considerably more severe in the latter group. One rat from group D also had middle ear changes, as reflected by a tilting of the head. Fluid intake was severely reduced in group D rats near the end of the 60-day experimental period and resulted in marked dehydration. Pathologic change (fatty liver) was observed at necropsy in only 1 rat from group D. Thiouracil treatment of rats reduced plasma thyroxine concentration to 48 to 68% of base line from experimental days 20 to 60. The same thiouracil treatment combined with feeding a manganese-deficient ration significantly reduced plasma thyroxine concentrations to 37% of base line at day 20 and 5% of base line at day 40; the concentration at day 60 was 76% of base line, apparently approaching normal because of concentration of the plasma (and thyroxine) in the dehydrated rats. Mean adrenal gland weight was significantly less than normal in group D rats, whereas mean thyroid gland weight in this group was increased, although less than that of group B rats treated with thiouracil only. Thus, clinical signs of deficiency were enhanced when athyreotic and manganese-deficient states were combined, and plasma thyroxine concentrations were markedly decreased, giving added meaning to the need for awareness of hormonal and trace mineral status of animals.

Animals↗
PubMed1989

Effects of hypothyroidism on vascular 125I-albumin permeation and blood flow in rats.

Effects of hypothyroidism on vascular 125I-albumin permeation and on blood flow were assessed in multiple tissues of male Sprague-Dawley rats rendered hypothyroid by dietary supplementation with 0.5% (wt/wt) 2-thiouracil or by thyroidectomy. In both thiouracil-treated and thyroidectomized rats, body weights, kidney weight, arterial blood pressure, and pulse rate were decreased significantly v age-matched controls. After 10 to 12 weeks of thiouracil treatment, 125I-albumin permeation was increased significantly in the kidney, aorta, eye (anterior uvea, choroid, retina), skin, and new granulation tissue, remained unchanged in brain, sciatic nerve, and heart, and was decreased in forelimb skeletal muscle. A similar pattern was observed in thyroidectomized rats, except that increases in 125I-albumin permeation for all tissues were smaller than those observed in thiouracil-treated rats, and 125I-albumin permeation in retina did not differ from controls. In both thiouracil-treated and thyroidectomized rats, changes in blood flow (assessed with 15-microns, 85Sr-labeled microspheres) relative to the decrease in arterial blood pressure were indicative of a decrease in regional vascular resistance except in the choroid and in the kidney, in which vascular resistance was increased significantly. Glomerular filtration rate was decreased, but filtration fraction and urinary excretion of albumin remained unchanged by thiouracil treatment and thyroidectomy. These results indicate that vascular hemodynamics and endothelial cell barrier functional integrity are modulated in many different tissues by the thyroid. In view of the correspondence of hypothyroid- and diabetes-induced vascular permeability changes, these results raise the possibility that altered thyroid function in diabetes may play a role in the pathogenesis of diabetic vascular disease.

Animals↗
PubMed1979

Binding of radioiodinated propylthiouracil to rat liver microsomal fractions. Stimulation by substrates for iodothyronine 5'-deiodinase.

Previous studies have shown that 2-thiouracil derivatives are uncompetitive inhibitors of iodothyronine 5'-deiodinase activity of rat liver microsomal fraction. Therefore the interaction of radioiodinated 6-propyl-2-thiouracil with rat liver microsomal fraction and the effect of substrate, cofactor and other inhibitors of 5'-deiodinase activity activity were investigated. It was found that micromolar concentrations of, in order of increasing potency, 3,5-diiodotyrosine, thyroxine, 3,3',5'-tri-iodothyronine and 3',5'-di-iodothyronine significantly enhanced binding of 5-[125I]iodo-6-propyl-2-thiouracil to the enzyme preparation. This stimulation was not seen in the presence of 1 mM dithiothreitol, 0.1 mM-6-propyl-2-thiouracil, 0.1 mM-6-propyl-2-thiouracil, 0.1 M-2-mercapto-1-methylimidazole or 1 mM-sodium sulphite. These results support the hypothesis that thiouracil derivatives inhibit 5'-deiodinase activity by forming a mixed disulphide with an intermediate enzyme complex, probably a sulphenyl iodide.

Animals↗
PubMed1983

Detection of melanomas. Approach with radiolabeled false precursors of melanin synthesis.

Thiouracil is a thiol-containing pyrimidine that is selectively incorporated into cells that synthesize melanin. In an effort to delineate further the specificity and dynamics of uptake, we injected thiouracil labeled with radioactive carbon into S91 melanoma-bearing mice; biopsy specimens were taken of the tumors and organs at various time intervals thereafter. The data showed a substantial uptake of thiouracil by the melanomas, with peak uptake occurring at 24 hours. All other organs examined showed only minor amounts of radioactivity, which probably reflected the presence of thiouracil in the blood perfusing these tissues. Because of its incorporation into melanomas, the use of radioactive thiouracil has potential as a marker for tumor growth, as a diagnostic tracer compound, and as a carrier for chemotherapeutic agents.

Animals↗
PubMed1988

Effect of hypothyroidism on methylmalonate excretion and hepatic vitamin B-12 levels in rats.

The effect of hypo- and hyperthyroidism on vitamin B-12 metabolism in the rat was studied by measuring methylmalonic acid excretion, B-12 content of liver and oxidation of 2-[14C]histidine. Ten percent pectin was added to increase severity of B-12 deficiency. The addition of thiouracil to a diet containing 10% pectin decreased the excretion of methylmalonic acid suggesting an amelioration of the B-12 deficiency. It was found that part of this decreased methylmalonic acid excretion was due to a decreased food consumption with a correspondingly decreased intake of branched-chain amino acids which are precursors of methylmalonic acid. When attempts were made to increase the protein intake of animals receiving thiouracil so their amino acid intake was equal to that of the control animals, methylmalonic acid excretion was still lower than that of the controls. It was also found that the vitamin B-12 content of the liver was higher in the animals receiving thiouracil than in the controls. Thyroidectomy had the same effect as feeding thiouracil. Liver B-12 levels are rapidly depleted on a B-12 deficient diet containing 10% pectin. It appears that hypothyroidism, induced either by thyroidectomy or by feeding thiouracil, slows the rate of depletion of hepatic B-12 which in turn facilitates the metabolism of methylmalonic acid and decreases its excretion in the urine.

Animals↗
PubMed1997

Supplemental thyroid hormones and molting in turkey breeder hens.

The objective of the current study was to determine whether thyroid physiology may affect molting time in turkeys. Two trials using approximately 144 hens were conducted to elucidate thyroidal factors that limit the molting process. Thyroid hormones or a thyroid blocker (thiouracil) were given to the hens during a molt by supplementing the diet with thyroxine (T4), triiodothyronine (T3), or thiouracil. Supplementing with T4 reduced the number of days to return to egg production, whereas supplementing with thiouracil or T3 prolonged days to first egg. The observations support previous suggestions of separate functions for T3 and T4 during molting. As had been observed many times previously, the feeding of thiouracil delayed the molt but did not completely stop the molting process. The hens fed thiouracil returned to 50% egg production nearly 10 d after the control group, whereas T3 prolonged the return to 50% egg production nearly 1 wk later. The data indicate the endogenous low levels of T4, but not T3 in modern strains of turkeys may contribute to a relatively longer molting period of turkey breeder hens induced to molt out of season.

Analysis of Variance↗
PubMedDate not supplied

Melanin-affinic thioureas as selective melanoma seekers.

2-Thiouracil and some related thioureas are receiving growing interest as selective melanoma seekers. They are incorporated into growing melanin, apparently due to covalent binding to dopaquinone, and the adduct is gradually trapped in the melanin polymer during its formation. To be clinically useful in melanoma scanning, thiouracil has been radioiodinated, and 5-iodo-2-thiouracil (ITU) was found to be localized in melanotic melanoma as selectively as thiouracil. Clinical trials with ITU, for the detection of malignant melanoma, are in progress, and the results so far are promising. Treatment with [35S]thiouracil has been performed on melanoma-bearing mice. The radiodoses needed for cure, however, were very high, which makes clinical application hazardous. Boron neutron capture therapy, on the other hand, might be a better approach. The technique is based on the irradiation of tumours with slow neutrons from an external source after the accumulation of boron in tumour tissue and clearance from normal tissues. Boron-10 undergoes instantaneous nuclear fission through the reaction 10B(n,alpha)7Li, and the emitted particles are efficient in cell killing. Boronated thioureas have been synthesized in various laboratories, and data from experiments on melanoma-bearing mice indicate that some of these compounds accumulate in the tumours in concentrations necessary for successful treatment.

Animals↗
PubMed1977

Pseudouridine-deficient transfer RNAs from Escherichia coli B and their use as substrates for pseudouridine synthetase.

Transfer RNAs isolated from Escherichia coli B grown in the presence of 2-thiouracil are deficient in pseudouridine. Much of this deficiency is from the T psi C region, which has only about 50% of its normal pseudouridine content. The other modified nucleoside from this region, ribothymidine, is reduced by only about 10%. Studies showed that 2-thiouracil is incoproated into the RNA of E. coli during growth in the presence of the analog. This incorporation appears to result from the replacement of uracil, occur in a random manner, and involve all RNA species. The extent of incorporation varies from 1 to 3 mol %, depending upon the preparation and RNA species examined. Electrophoresis on polyacrylamide gels and chromatography on Sephadex G-75 and reverse phase (Systen 5) columns of normal and 2-thiouracil-containing tRNAs revealed no profile differences. No accumulation of any precursor tRNA in the thiopyrimidine-treated cells is found. A partial recovery of the pseudouridine content of 2-thiouracil-containing tRNAs can be achieved in vivo by removal of the 2-thiouracil from the culture media. These transfer RNAs have also been used as substrates to study the properties of a partially purified preparation of pseudouridine synthetase II invitro and should be useful as substrates in the further purification of this enzyme.

Escherichia coli↗
PubMed2006

Influence of thioketo substitution on the properties of uracil and its noncovalent interactions with alkali metal ions: threshold collision-induced dissociation and theoretical studies.

Experimental and theoretical studies are carried out to determine the influence of thioketo substitution on the properties of uracil and its noncovalent interactions with alkali metal ions. Bond dissociation energies of alkali metal ion-thiouracil complexes, M(+)(SU), are determined using threshold collision-induced dissociation techniques in a guided ion beam mass spectrometer, where M(+) = Li(+), Na(+), and K(+) and SU = 2-thiouracil, 4-thiouracil, 2,4-dithiouracil, 5-methyl-2-thiouracil, and 6-methyl-2-thiouracil. Ab initio electronic structure calculations are performed to determine the structures and theoretical bond dissociation energies of these complexes and provide molecular constants necessary for thermodynamic analysis of the experimental data. Theoretical calculations are also performed to examine the influence of thioketo substitution on the acidities, proton affinities, and A::SU Watson-Crick base pairing energies. In general, thioketo substitution leads to an increase in both the proton affinity and the acidity of uracil. 2-Thio substitution generally results in an increase in the alkali metal ion binding affinities but has almost no affect on the stability of the A::SU base pair. In contrast, 4-thio substitution results in a decrease in the alkali metal ion binding affinities and a significant decrease in the stability of the A::SU base pair. In addition, alkali metal ion binding is expected to lead to an increase in the stability of both single-stranded and double-stranded nucleic acids by reducing the charge on the nucleic acid in a zwitterion effect as well as through additional noncovalent interactions between the alkali metal ion and the nucleobases.

Journal Article↗
PubMed1983

Thioamides as false melanin precursors: studies in murine melanomas.

Melanotic melanomas show a high rate of melanin synthesis. Foreign substances that are accepted as precursors in the formation of melanin may therefore be useful in the diagnosis and therapy of malignant melanotic melanomas, if labelled with suitable radionuclides. We have earlier reported that 2-thiouracil is incorporated in melanotic melanomas, apparently as a false melanin precursor. In the present study it is shown that methimazole and 5-iodo-2-thiouracil are as well accepted as melanin precursors. 5-Iodo-2-thiouracil is of special interest, since iodine has many clinically useful radioisotopes. The chemical properties that characterize substances which are incorporated as false precursors into melanin are discussed. A free sulfur ligand of the thioamides (2-thiouracil, 5-iodo-2-thiouracil, methimazole and thiourea are all incorporated into melanin) seems to be essential and the link between these substances and the melanin. Uracil (which lacks sulfur) and 2-benzylthiouracil (where the sulfur is blocked with a benzyl group) do not attach to melanin. Our conclusion therefore is that the thioureylene structure is the smallest common molecular fragment of the false melanin precursors.

Amides↗
PubMed1996

Modulation by thyroid hormones of the development of external plexiform layer in the rat olfactory bulb.

Width of the external plexiform layer in olfactory bulbs and mean area of mitral and granule cell dendritic and glial processes were measured of normal, hypo- and hyperthyroid rat pups at the age of 24 days. Hypothyroidism was induced by treating the rats with a reversible goitrogen 6-n-propyl-2-thiouracil dissolved in their drinking water, while the hyperthyroid group was given water containing thyroxine. The 6-n-propyl-2-thiouracil treatment was begun on gestational day 18 and on the day of birth. Thyroxine treatment started on the day of birth. Both treatments were continued till the day of sacrifice. A significant decrease in the width of the external plexiform layer of the olfactory bulb in the prenatally 6-n-propyl-2-thiouracil treated group and a significant increase in the width of the external plexiform layer of the hyperthyroid group was shown by the Student's paired t-test. The areas of neuronal and glial processes were measured at electron microscopic level by using an IBAS image analysing system. A significant decrease was found by the Kruskal-Wallis test and Dunn's range test in the mean area of (1) mitral cell dendrites in the prenatal 6-n-propyl-2-thiouracil treated group, (2) granule cell dendrites in both the postnatally 6-n-propyl-2-thiouracil treated and in the hyperthyroid groups and (3) glial processes in the thyroxine treated group comparing to controls.

Animals↗
PubMed1998

Biotransformation of several structurally related 2B compounds to reactive metabolites in the somatic w/w+ assay of Drosophila melanogaster.

Biotransformation of several structurally related 2B compounds to reactive metabolites was evaluated in the somatic w/w+ assay of Drosophila melanogaster. Chemicals tested were the dichlorinated alkanes dichloromethane (DCM), 1,2-dichloroethane (DCE), and 1,3-dichloropropane (DCP); the thiouracil derivatives 5-methyl, 2-thiouracil (5M2TU), 6-methyl, 2-thiouracil (6M2TU), and 5-propyl, 2-thiouracil (5P2TU); and the plastic monomer styrene (STY) and its metabolite styrene 7,8-oxide (SO). The tester strains used consisted of one wild-type insecticide-susceptible (IS) laboratory strain (Leiden-S, ST), and two insecticide-resistant (IR) strains (Hikone-R, HK, and Haag-R, HG). The latter have high cytochrome P450-dependent bioactivation capacities. Drosophila larvae heterozygous for the wild-type report gene w+ were exposed chronically to at least three different exposure doses of each compound. A total of 53,694 eyes were analyzed. A positive genotoxic activity was obtained for DCM and for 6M2TU at all exposure doses and genotypes analyzed, and for SO in the IR strains HK-R and HG-R. An overall weakly recombinagenic response was shown by DCE and 5M2TU. The chemicals DCP, 5P2TU, and STY proved to be overall negative in IR as well as in IS strains, and SO was negative in the standard stock. Biotransformation mediated by cytochrome P450 monoxigenases to reactive metabolites is discussed.

Animals↗
PubMed1976

Perinatal hypothyroidism in rats: persistent motivational and metabolic effects.

Five groups of female rats which were exposed to thiouracil for varying periods around the time of birth were compared with a 6th group of untreated controls in motivational, metabolic, and hormonal test situations during adolescence and adulthood. The thiouracil-treated rats displayed reduced fearfulness in lever-touching and lever-pressing tasks in operant conditioning chambers and in their initial adaptation to activity-wheel and maze apparatuses. These rats also showed hyperactivity in asymptotic running-wheel performance, increased spontaneous recovery of extinguished lever-pressing, and elevated responding in lever-pressing for variable-interval food reinforcement. A supplemental study revealed significantly greater ad libitum food and water intake and oxygen consumption in male thiouracil-treated rats and elevated serum thyroxine levels in thiouracil-treated females. In general the results indicate that perinatal thyroid deficiency engenders a chronic hypermetabolic state in both sexes which may be associated with a persistent, mild hyperthyroid condition in the case of female rats.

Animals↗
PubMed1979

Mechanism of action of iodothyronine-5'-deiodinase.

Production of 3,3'-di-iodothyronine (3,3'-T2) from 3,3',5'-tri-iodothyronine (reverse T3, rT3) as catalysed by rat liver microsomal fraction was measured with a specific radioimmunoassay. The effect of the addition of 2-thiouracil and of varying concentrations of cofactor (dithiothreito) on the kinetic parameters of this reaction were studied. It was found that thiouracil is an uncompetitive inhibitor with respect to substrate and a competitive inhibitor with respect to cofactor. The effect of a decrease in the concentration of cofactor was similar to the effect of addition of thiouracil, i.e. a proportional decrease in Km and V. The results strongly suggest that enzymatic 5'-deiodination of iodothyronines follows a ping-pong mechanisms, which may be envisaged as a transiodination and the subsequent reduction of the iodo-enzyme complex by cofactor. The intermediate is probably a sulfenyl iodide form of the enzyme, which reacts with thiouracil to yield a mixed disulfide.

Animals↗
PubMed1980

Mechanism of inhibition of iodothyronine-5'-deiodinase by thioureylenes and sulfite.

Previous studies have demonstrated that thiouracil inhibits the 5'-deiodination of 3,3',5'-triiodothyronine uncompetitively with respect to substrate and competitively with respect to cofactor (thiol compounds). This paper shows that sulfite is also a strong inhibitor of this reaction showing a dose-dependent effect between 1 microM and 1 mM. The mode of inhibition is similar to that described for thiouracil. Dose-dependent inhibition was also observed with thiosulfate (0.01-1 mM), iodide and thiocyanate (both greater than 1 mM). No effect was exerted by up to 10 mM cyanide and up to 100 mM azide. Methimazole and thiourea were weak inhibitors above 0.1 mM but inhibition did not reach completion. These experiments were carried out in the presence of 1 mM dithiothreitol. The effect of thiouracil was found to be competitively obviated by methimazole and thiourea. However, the effect of sulfite and that of methimazole or thiourea were additive. It is proposed that an enzyme-sulfenyl iodide is formed during deiodination (ping-pong mechanism). This sulfenyl iodide may be reduced by cofactor to yield native enzyme. It may also react with thioureylenes, yielding mixed disulfides, or with sulfite, yielding a thiosulfate. The enzyme-methimazole disulfide is apparently less stable than the enzyme-thiouracil complex. It is suggested that sulfite also reacts with the enzyme-thioureylene disulfide.

Animals↗
PubMed1987

Organ weights, T-cell proliferation, and graft vs host capabilities of hypothyroidic chickens.

Thiouracil-induced hypothyroidism reduced the thymus weights of young chickens. Thyroid weights were greater in thiouracil-fed (TF) chicks, and the circulating levels of triiodothyronine and thyroxine were lower. Thiouracil treatment resulted in higher relative adrenal weights and serum corticosterone concentrations. Absolute weights of adrenals were equivalent between control and TF groups. The TF chicks showed depressions of total white blood cell counts and numbers of lymphocytes. Monocyte and granulocyte numbers were unchanged from those of controls. Thiouracil treatment lowered the phytohemagglutinin M responsiveness of peripheral blood leukocytes (PBL). On the other hand, the PBL from TF chicks produced the higher graft vs host (GvH) response. Therefore, while the hypothyroidic state impaired cycling activity in T cells, this condition did not significantly influence a functional parameter of T cells, the GvH response.

Animals↗
PubMed1990

Stimulation of oxidative metabolism by thyroid hormones in an apodan amphibian, Gegenophis carnosus (Beddome).

Administration of different doses of L-thyroxine (T4) and triiodo-L-thyronine (T3) in vivo in G. carnosus stimulated the activities of cytochrome oxidase, alpha-glycerophosphate dehydrogenase (alpha-GPDH), succinate dehydrogenase (SDH), and Mg2+ adenosine triphosphatase (Mg2+ ATPase) and inhibited the activity of malate dehydrogenase (MDH). While a low dose of thiouracil administration produced a stimulatory effect on cytochrome oxidase and alpha-GPDH activities, a higher dose of thiouracil significantly inhibited the activities of cytochrome oxidase, alpha-GPDH, SDH, Mg2+ ATPase, and MDH. Injection of T4 or T3 into thiouracil-treated animals significantly restored the stimulatory effect of thyroid hormones on oxidative enzyme activities. It is suggested that thyroid hormones in vivo increase and that thiouracil decreases the oxidative capacity of hepatic mitochondria of G. carnosus.

Amphibians↗
PubMed2005

Simultaneous determination of thyreostatic residues in animal tissues by matrix solid-phase dispersion and gas chromatography-mass spectrometry.

A method for determination of thyreostatic residues in animal tissues by matrix solid-phase dispersion (MSPD) and gas chromatography-mass spectrometry in selected ion detection mode was developed. Thyreostatic compounds in different matrices were extracted and purified by combination of MSPD and subsequent solid-phase extraction. Silica gel was selected as the solid support of both procedures and the conditions of the procedures were optimized. Thyreostats were derivatized with pentafluorobenzylbromide (PFBBr) in strong basic medium and then with N-methyl-N-(trimethylsilyl)-trifluoroacetamide (MSTFA), which can improve the yields of derivatization for thyreostats, the repeatability, and therefore the limits of detection (LOD) of thyreostats. The limits of detection reached 10 microg/kg (2-thiouracil, 6-methyl-2-thiouracil and 6-propyl-2-thiouracil), 20 microg/kg (6-phenyl-2-thiouracil) and 50 microg/kg (tapazole) with high recoveries (more than 70% for most of thyreostats) and relative standard deviations between 4.5% and 8.7%.

Acetamides↗