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PubMed1983

Perinatal thiouracil exposure depresses corticotropin-releasing factor activity in 15 day old rats.

Although previous in vivo studies have shown thiouracil to delay maturation of the hypothalamus-pituitary-adrenal (HPA) axis response to stress, the nature of the developmental deficit was not determined. By in vitro methods we determined which HPA components are influenced by thiouracil-induced hypothyroidism in 15 day old rats. Our results indicate that adrenal response to ACTH stimulation and adenohypophysial ACTH content were not significantly modified by thiouracil exposure. On the other hand, the corticotropin-releasing factor-like activity of median eminence extracts was severely depressed by thiouracil-induced hypothyroidism. Thus, the delayed maturation of functional capacity of the central nervous system caused by hypothyroidism includes synthesis of biologically active corticotropin-releasing factor.

Adrenocorticotropic Hormone↗
PubMed1981

Incorporation of thiouracil and some related compounds into growing melanin.

Several drugs, mainly polycyclic amines, are accumulated in melanin-containing tissues. They are bound to preformed melanin (both in vivo and in vitro). Thiouracil is accumulated into melanin according to another principle: It is incorporated as a false precursor during melanin formation. It is thus taken up only in growing melanin, e.g. in the eye of pigmented mouse foetuses or in melanomas. The acceptance of a foreign substance during the formation of a foetal tissue seems theoretically important. We are also interested in the practical viewpoint of using false melanin precursors as selective melanoma seekers. Some related substances are therefore compared with respect to incorporation into growing melanin. The thiouracil uptake in the ocular melanin of a 5 day old mouse was 276 times higher than that of a 3 month old mouse based on weight units of melanin. Thiourea is incorporated in growing melanin as well but also binds slightly to preformed melanin. Uracil and fluorouracil showed no specific uptake into growing melanin. It thus seems as if the sulfur is essential for the incorporation into the melanin polymer. 35S-thiouracil and 2-thio(2-14C)urcal showed the same high uptake, indicating that at least part of the uracil moiety is incorporated together with the sulfur. There seems to be a relation between the property to be incorporated into melanin and the tyrostatic activity. Both in the formation of melanin and thyroid hormones, tyrosine is the physiological precursor and both reactions are catalyzed by oxidizing enzymes. Properly labelled thiouracil derivatives seem to be promising melanoma seekers for diagnostic and radiotherapeutic purposes.

Animals↗
PubMed1977

Differential effect of 2-thiouracil on synthesis of two plant viruses in the same host.

In cowpea leaves singly or doubly infected with cowpea chlorotic mottle virus (CCMV) and/or southern bean mosaic virus (SBMV), treatment with 2-thiouracil increased the accumulation of CCMV particles and strongly decreased the accumulation of SBMV particles. Thiouracil prevented the usual inhibition of synthesis of CCMV particles at about 6 days after inoculation, and 2-3 times as many CCMV particles accumulated as in water-treated plants. A single treatment of thiouracil 48 h before, at the time of, or 24 h after inoculation caused at least 90% decrease in the amount of SBMV particles extracted from inoculated leaves for at least 15 days. When virus particles were extracted from plants treated with thiouracil, the specific infectivity of CCMV was increased 2.3 times and SBMV was decreased 0.46 times as compared to virus from control plants.

Mosaic Viruses↗
PubMed1983

Effect of 2-thiouracil on RNA and protein synthesis in synchronous and asynchronous infections of tobacco mosaic virus.

Examination of the effect of 2-thiouracil on tobacco mosaic virus (TMV) RNA and protein synthesis in synchronous and asynchronous systems of replication in tobacco leaves demonstrated that 2-thiouracil does not prevent synthesis of TMV RNA, as suggested by previous studies, but inhibits some earlier function. When added at different times after mechanical inoculation, 1 mM 2-thiouracil partially inhibited both viral RNA and protein synthesis, with greater inhibition when treatment began nearer the time of inoculation. In leaves systemically inoculated with TMV using a differential temperature inoculation procedure to synchronize the infection, 1 mM 2-thiouracil inhibited viral protein and RNA synthesis totally when treatment began within the first 4 h after initiation of replication, but not at all when treatment began at 12 h or later, even though earlier reports had shown that most RNA and protein synthesis occurred after 12 h.

RNA, Viral↗
PubMed1980

Effects of dietary ascorbic acid, aspirin, lysine, and thiouracil on thyroid activity.

Broiler chickens were reared in batteries and fed diets designed to determine the effects of either ascorbic acid, aspirin (acetylsalicylic acid), lysine, or thiouracil on thyroid weight and serum thyroid hormone concentrations. Thyroxine (T4) and 3,5,5'-triiodothyronine (T3) concentrations in serum were determined by radioimmunoassay. Neither ascorbic acid nor lysine affected T3 or T4 concentration, but thiouracil significantly reduced T3 concentration after 1 day and reduced T4 concentration after 3 days. After 3 days or more of thiouracil feeding, relative reduction was greater for T4 than T3. Dietary aspirin significantly reduced T3 concentration at 7 of 16 sampling times but significantly reduced T4 concentration at only 1 of 16 sampling times. After 11 days of the dietary treatment, chickens fed thiouracil had significantly heavier thyroids than the controls but ascorbic acid, aspirin, and lysine had no effect on thyroid weight.

Animals↗
PubMed1983

Effect of thiouracil on response to heat stress of White Leghorn lines selected for fast and slow gain in two temperatures.

Four lines of White Leghorns previously selected for fast and slow gain from 5 to 9 weeks of age in a hot (32.2 C) and in a cold (21.1 C) selection environment were grown from 5 to 9 weeks in the same two temperature environments. Samples of 32 females from each line of the third generation grown in each temperature environment from 5 to 9 weeks of age were divided into two groups; one received .2% thiouracil in the diet for a 5-day period and the other did not. The temperature was then increased to 40.6 C until 52.8% of all birds had died. The percentages of mortality of lines, rearing environments, and thiouracil treatments were then analyzed. An increase of 64.8% mortality from acute heat stress for birds reared in the cold environment was significant, but the differences among the four selected lines were not. The presence of thiouracil in the diet significantly reduced mortality from heat stress by 16.4%. There were no significant interactions between thiouracil treatments and selected lines or rearing environments.

Acclimatization↗
PubMed1985

Effect of thiouracil-induced hypothyroidism on the humoral immunity of New Hampshire chickens.

Two experiments were conducted to examine the effects of feeding a diet containing .1% thiouracil to two lines of New Hampshire chickens differing in growth rate and relative bursa size. Body weight, serum 3,5,3'-triiodothyronine, and thyroxine were reduced by the thiouracil treatment. The primary total anti-sheep red blood cell (SRBC) titer in Experiment 1 was higher for thiouracil-fed (TF) chicks at 7 days postprimary immunization (PPI). In Experiment 2, the total anti-SRBC titers were higher for control chicks 3 days PPI; but from 5 to 10 days PPI, TF chicks had higher titers. During the secondary response in both experiments, the total anti-SRBC titers were not consistently higher for one dietary group over the other from 3 to 10 days postimmunization. Mercaptoethanol-resistant antibody titers were not significantly different between the two dietary groups in either experiment during the primary and secondary responses. Thiouracil-fed chicks had higher immunoglobulin G (IgG) and M (IgM) concentrations in serum during both the primary and secondary responses in Experiment 2. Although there was no genotype effect on antibody production to SRBC, serum immunoglobulins were different between lines. Small bursa line (SBL) chickens had higher serum IgG while the IgM concentrations of chicks from the Lester J. Dreesen strain were greater than those of SBL.

Animals↗
PubMed1983

Incorporation of [125I]-5-iodo-2-thiouracil in cultured hamster, rabbit, and human melanoma cells.

The incorporation of [2-14C]-2-thiouracil and a series of [125I]-5-iodo-2-thiouracils ([125I]ISUra(s)) into cultured Greene hamster melanoma cells was determined in order to establish their properties as false precursors in the melanin-biosynthetic pathway. The cold trichloroacetic acid-precipitable incorporation of [2-14C]-2-thiouracil as well as [125I]ISUra into melanoma cells after a 24- to 48-hr labeling period proved to be completely tyrosinase dependent (more than 99.5% inhibition could be achieved by 0.5 mM phenylthiourea). [125I]ISUra incorporation was 3-fold higher than was [2-14C]-2-thiouracil incorporation and was enhanced by 1 mM theophylline treatment. [125I]ISUra incorporation into hamster, rabbit, and human melanoma cells showed a linear relationship with cell melanin content. Methylation of the sulfur completely prevented the incorporation, while propylation but not methylation at position 6 resulted in lower incorporation. [125I]ISUra proved to be a marker for melanogenesis and may be useful in studies on the differentiation of cultured melanoma cells.

Animals↗
PubMed1982

Altered growth patterns and depressed pituitary growth hormone content in young rats: effects of pre- and postnatal thiouracil administration.

The important influence of postnatal thyroid status on development is well recognized, while the effect of prenatal thyroid status on postnatal growth is less understood. The present study was undertaken to assess the effects of pre- and postnatal thiouracil administration on postnatal growth and pituitary grown hormone (GH) content in 25 day old rats. Pups were born to Sprague-Dawley rats fed lab chow mash containing 0.25% thiouracil according to the following schedules: a) during gestation only; b) during lactation only (25 days postpartum); and c) through gestation and lactation. Mothers of euthyroid controls were fed diet without thiouracil for the length of the experiment. Pups were weighed daily through day 21 and decapitated on day 25. Pituitary GH content was measured by densiometric comparison of disc gel column electrophoresed pituitary homogenates with similarly treated rat GH standard. Incorporation of thiouracil into the diet of pregnant and/or lactating rats significantly depressed the body weight and pituitary GH levels in their 25 day old pups. Furthermore, analysis of the daily mean body weight of each litter revealed four significantly different patterns of growth. While previous investigators have reported that prenatal thyroid restriction does not significantly alter the developmental processes of young rodents, the present study indicates that prenatal thyroid status is an important influence on normal postnatal growth.

Analysis of Variance↗
PubMed1993

Effect of thiouracil-induced hypothyroidism on time course of adrenal response in 15 day old rats.

Previous investigations have supported the suggestion that perinatal induction of hypothyroidism, using the goitrogen thiouracil, completely prevents elevation of circulating corticosterone levels 15 min after ether stress in 15 day old rats. The present study used radioimmunoassay (RIA) to evaluate the effect of chemical hypothyroidism on response of circulating corticosterone to ether stress, or to exogenous corticotropin releasing factor (CRF), at 15, 30, or 45 min after stimulation. Fifteen day old hypothyroid rat pups responded to ether stress with a linear increase in circulating corticosterone over the time course of the study, and with the levels at 30 and 45 min significantly greater than unstimulated. However, the slope of the increase was markedly subnormal, as was corticosterone level at each time point after stress. On the other hand, CRF injection resulted in elevations of corticosterone along the time course that were similar for normal and thiouracil exposed rats. The results of this study do not support the previous conclusion that chemical hypothyroidism entirely abolishes adrenal axis response in 15 day old rats. Instead, thiouracil depresses the response at a number of post-stimulation time points, rather than causing a time-dependent delay in a normal corticosterone elevation. This is likely the result of thiouracil-induced functional deficits in all components of the neuroendocrine axis regulating corticosterone secretion, with particularly severe effects at the hypothalamus.

Adrenal Glands↗
PubMed2001

Thiouracil antithyroid drugs as a new class of neuronal nitric oxide synthase inhibitors.

Two established antithyroid drugs, 6-propyl-2-thiouracil and 6-methyl-2-thiouracil, as well as S-methylthiouracil, are shown to be competitive inhibitors of nitric oxide synthase (NOS) (K(I) values ranging from 14 to 60 microM), with moderate selectivity for the neuronal isoform. Other thioureylene and thioamide-containing heterocyclic systems proved virtually ineffective as NOS inhibitors. Besides offering novel useful leads for inhibitor design as well as to probe the active site of neuronal NOS, the results of this study may have interesting implications in relation to the antithyroid activity of thiouracils and their possible neurological effects.

Animals↗
PubMed1981

Substrate requirement for inactivation of iodothyronine-5'-deiodinase activity by thiouracil.

Preincubation of rat liver microsomal fraction with 1 microM 2-thiouracil and 0.01-1 microM 3,3',5'-triiodothyronine or 3',5'-diiodothyronine, 0.1-10 microM thyroxine or 3,5-diiodothyronine led to a progressive, irreversible and concomitant decrease in subsequently assayed 3,3',5'-triiodothyronine- and 3',5'-diiodothyronine-5'-deiodinase activity. Preincubation with thiouracil alone, with iodothyronines alone or with thiouracil and 10 microM thyronine or 3,5-diiodotyrosine had no or virtually no effect. The results indicate that (1) a previously proposed ping-pong mechanism for thyroid hormone deiodination, involving the formation of an enzyme-sulphenyl iodide intermediate, is correct; (2) thyroxine, 3,3',5'-triiodothyronine and 3',5'-diiodothyronine are substrates for a common 5'-deiodinase; (3) this 5'-deiodinase is not fully specific as regards the position of the iodine substituents in the substrate, since it also appears to catalyse the 5-deiodination of 3,5-diiodothyronine.

Animals↗
PubMed1976

Inhibition of Bacillus subtilis DNA polymerase III by arylhydrazinopyrimidines. Novel properties of 2-thiouracil derivatives.

6-(p-Tolylhydrazino)-uracil, 6-(p-tolylhydrazino)-isocytosine and 6-(p-tolylhydrazino)-2-thiouracil were synthesized and compared with respect to their chemical properties, their activity as inhibitors of DNA polymerase III of Bacillus subtilis, and their capacity to induce the formation of a complex between polymerase III and template DNA. As expected from earlier studies of analogous hydroxyphenylhydrazino compounds, the effects of the uracil derivative were reversed specifically by dGTP and those of the isocytosine derivative were reversed specifically by dATP. In contrast, reversal of the effects of the thiouracil derivative required both dGTP and dATP. The unique capacity of the 2-thiouracil analog to mimic either purine deoxyribonucleotide appears to reside in its ability to undergo tautomerism between the 2-thione and 2-thiol forms, which can pair with, respectively, template cytosine and thymine.

Bacillus subtilis↗
PubMed1989

Therapeutic effects of S-35-thiouracil in BALB/c mice carrying Harding-Passey melanoma.

Thiouracil (TU) selectively binds to the pigment melanin during melanogenesis and is rapidly cleared from normal tissues. This compound shows little affinity for pre-formed melanin. BALB/c mice, carrying the subcutaneously transplanted Harding-Passey melanoma, were given i.p. injections of 35S-labeled thiouracil in a range of doses and administration schedules. Injected doses ranged from 1.3 to 10 mCi per mouse with resultant tumor dose rates of 10 to 30 cGy/hr, respectively. At the lower dose rates, growth delay of approximately 1 to 2 weeks was observed in all tumors. At the highest doses used, complete tumor regression (no regrowth) was observed in some cases, with extended growth delays of approximately 6 weeks in the rest. These results illustrate the possible utility of radiolabeled thiouracil as a systemically administered brachytherapy agent for melanoma.

Animals↗
PubMed2002

The antithyroid agent 6-n-propyl-2-thiouracil is a mechanism-based inactivator of the neuronal nitric oxide synthase isoform.

6-n-Propyl-2-thiouracil (6-PTU), the antithyroid agent, produces a time-, concentration-, and turnover-dependent inactivation of the NO synthetic capability of the neuronal nitric oxide synthase isoform irreversible by either arginine or (6R)-5,6,7,8-tetrahydro-L-biopterin. By contrast 6-PTU produces an inhibition of the cytokine-inducible and endothelial nitric oxide synthases fully reversible by arginine. The inactivation of neuronal nitric oxide synthase by 6-PTU follows first order kinetics, and is inhibited competitively by both arginine and (6R)-5,6,7,8-tetrahydro-L-biopterin, but is not accompanied by either a loss of heme-CO binding, heme fluorescence, or disassembly of dimeric structure. 2-Thiouracil behaves qualitatively identically to 6-PTU. Turnover-dependent inactivation of neuronal nitric oxide synthase by [2-14C]-2-thiouracil is accompanied by incorporation of radioactivity into the polypeptide chain. Ca2+-dependent NO formation by GH3 pituitary cells is inhibited by 6-PTU in a manner enhanced by depletion of either extracellular arginine or intracellular (6R)-5,6,7,8-tetrahydro-L-biopterin. These observations establish that 6-PTU is an alternate substrate, mechanism-based inactivator of the neuronal nitric oxide synthase isoform with the ability to suppress cellular NO formation.

Animals↗
PubMed1997

Protein dilution effect on thiouracil-seroalbumin interactions.

As the spectra and binding parameters calculated for the thiouracil-albumin interaction change with the protein concentration, a human seroalbumin conformational change depending on protein concentration has been suggested. This protein-conformational change is tested by dilatometry and viscosimetry. At low concentrations, albumin showed a greater thiouracil binding capacity and a second positive peak in its interaction with the drug, detected by difference spectroscopy. Both effects are due to a monomerisation of protein dimers and not to a conformational change depending on protein concentration. This monomerisation would imply a major accessibility of thiouracil and propylthiouracil to other binding sites on HSA.

Binding Sites↗
PubMed2003

Application of improved iodine-azide procedure for the detection of thiouracils in blood serum and urine with planar chromatography.

The application of iodine-azide reaction for the determination of thiouracils in thin-layer chromatography and high-performance thin-layer chromatography is described. The developed plates were sprayed with a freshly prepared mixture of sodium azide, adjusted to a proper pH, and starch solution, and exposed to iodine vapour for 5 s. The detection limits were established at pmol level. The factors depending on the detection limits were described. A comparison of iodine-azide tests reaction with other procedures is presented. The developed method was applied to detection of thiouracils in blood serum and urine. The possibility of detection of a thiouracils mixture was demonstrated.

Azides↗