[Analytical studies on thiouracils. I. Synthesis and thin-layer chromatography of thiouracils (author's transl)].
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Chromatography, Thin Layer↗
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[Analytical studies on thiouracils. II. Dissociation constants of thiouracils and their reactions with hydrogen peroxide (author's transl)].
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Chemical Phenomena↗
X-ray photoelectron spectrometry of copper-thiouracil complexes.
X-ray photoelectron spectrometry was applied to evaluate the correct oxidation number of copper in complexes with 2-thiouracil, 6-amino-2-thiouracil and 6-methyl-2-thiouracil. Regardless of the mode of preparation exclusively Cu(I) was bound to the different thiouracil compounds, producing one homogeneous signal of the Cu2p3/2 electrons at 932.5 eV. Upon oxidation with H2O2, a typical Cu(II) satellite appeared in the main signal of the Cu2p3/2 level was shifted to higher binding energy values. The reaction of Cu(II) with thioracil yielded identical complexes as above, in which Cu had the formal oxidation state +I. During this reaction portions of the thiouracil were oxidized to 2,2'-dithiobis(4-pyrimidinol) [bis(4-hydroxy-2-pyrimidinyl)disulphide], as seen by the shifted sulphur 2p signals to 163.5 eV. After treating the Cu-thiouracil complexes with H2O2, the simultaneous presence of sulphur species having the oxidation states RStheta (161 eV), RSSR (163.5 eV) and RSOtheta3 (168.5 eV) is indicated by the ESCA signals monitored.
Copper↗
Effect of thiouracil upon canine arterial elastic tissue.
Unlike some other mammalian species, the dog is relatively resistant to the development of elevated levels of serum cholesterol after prolonged cholesterol feeding. This may be overcome by suppressing thyroid activity with thiouracil. Information regarding possible activity of thiouracil itself upon the arterial tissues is almost nonexistent. The present investigation was undertaken to test whether this drug has any such action, especially upon the arterial elastic tissues. Destructive changes were observed in arterial elastic tissues in dogs given thiouracil for three and six months. The changes consisted of accentuation of the elastic fibrillar components, formation and subsequent coalescence of clefts, and fragmentation and ultimate "dissolution" of the elastic elements. The results suggest that thiouracil may exert a damaging effect upon the arterial elastic fibers; thus, it is possible that one of the mechanisms by which thiouracil and cholesterol administration induces experimental atherosclerosis in the dog is by elastic tissue destruction, possibly promoting the subsequent lipid accumulation in the arterial wall.
Animals↗
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↗
[Sub-ppm determination of thiouraciles applicated as thyreostatics in meat by high pressure liquid chromatography (author's transl)].
The thyreostatics 2-thiouracile, 4-methyl-2-thiouracile, and 2-propyl-2-thiouracile were extracted from meat and determined by High Pressure Liquid Chromatography to a limit of about one ppb.
Animal Feed↗
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↗
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↗
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↗
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↗
The irreversible inactivation of thyroid peroxidase by methylmercaptoimidazole, thiouracil, and propylthiouracil in vitro and its relationship to in vivo findings.
A reinvestigation of the mechanism of action of methylmercaptoimidazole, propylthiouracil, and thiouracil on thyroid peroxidase (TPO) was undertaken. A preliminary incubation of TPO and H2O2 with methylmercaptoimidazole, propylthiouracil, or thiouracil was carried out in the absence of oxidizable substrates (i.e. I- or guaiacol). This incubation resulted in irreversible inactivation of TPO. The extent of inactivation could be determined after removal of the drug by gel filtration or by dilution into the assay mixture. Preincubation, as above, in the presence of iodide or thiocyanate prevented the irreversible inactivation of TPO. Rats receiving doses of these drugs which completely inhibited protein-bound iodine formation showed normal levels of TPO in their thyroid glands 30 min after drug administration. These findings suggest that the initial in vivo action of these drugs is to block iodination by trapping oxidized iodide, not by acting as "general inhibitors" of the TPO.
Animals↗
The influence of diazepam and thiouracil upon the carcinogenic effect of diethylnitrosamine in gerbils.
N-diethylnitrosamine (DEN) was simultaneously administered with diazepam (DZP) or thiouracil (TU) once weekly for life to gerbils (Meriones unguiculatus). Additional DZP or TU treatment increased significantly average survival time and inhibited the development of cholangiocarcinomas, although cholangiomas were still observed in these groups. Tumor type and incidence in the nasal cavities were not influenced by DZP or TU. However, in comparison to DEN alone tumor latencies were prolonged.
Adenoma, Bile Duct↗
Microbial formation of 4-thiouracil.
A soil organism identified as Streptomyces libani var. soldani was found to produce 4-thiouracil. The product was isolated in a yield of 150 mug/ml of filtered beer and characterized by C-13 magnetic resonance and high-resolution mass spectroscopy. The product has a broad antibacterial spectrum but low specific activity.
Bacillus subtilis↗
Accumulation of radioiodine in thiouracil-hyperplastic thyroids of chicks.
Kinetics of accumulation of radioiodine was studied in thyroids of chickens before, during, and following ingestion of 0.25% thiouracil (TU). After a latent period of about 5 days, weight of the thyroid gland increased, reaching its maximum (42 mg/100 g body wt) after 21 days of TU ingestion; thyroid weight decreased immediately on withdrawal of TU but tended to plateau at a higher level than that of controls. One-way clearance increased by day 4 of ingestion of TU and reached its peak early during hyperplasia; it very quickly reverted to a control level on withdrawal of TU. Exit-rate constant increased markedly during early hyperplasia and decreased to a level less than normal after withdrawal of TU. Concentration of 127I decreased by a factor of 18 by 2 wk of feeding TU; it increased to practically a normal level by 1 wk after withdrawal of TU.
Animals↗
Effect of thyroxine and thiouracil additions to diets containing rapeseed meal, on chick growth and carcass composition.
Experiments have been conducted to study the hypothyrotic status of chicks fed rapeseed meal. Protamone supplementation did not correct growth depression due to feeding rapeseed meal although inclusion levels up to 0.1% may have induced a hyperthyrotic condition which in itself leads to a growth depressing effect. Changes in liver and carcass composition were observed when diets containing rapeseed and soybean meal were supplemented with protamone and thiouracil. It is concluded that although birds fed rapeseed meal are abnormal with respect to thyroid metabolism, it is likely that factors other than a simple reduction in serum thyroxine concentration are responsible for the growth depression observed for such birds.
Animal Feed↗
Structural changes in the thyroid gland of buffalo following administration of thiouracil.
The effects of a goitrogen (thiouracil) on the structural variations of the thyroid gland were studied in male buffalo calves. Following the treatment, the thyroid became enlarged and both the weight and the size of the gland were significantly increased (P less than 0.01). Hyperplasia and hypertrophy of the gland were correlated with a significant increase of thyroidal uptake of 131I. The height and number of the follicular cells were significantly increased (P less than 0.01). The follicles were small and had vacuolations in the colloid. The colloid content of the follicles became reduced. The vascularity of the gland was appreciably increased.
Animal Feed↗
Effect of methyl thiouracil on radioiodine thyroidal retention in rats.
Some goitrogens like methyl thiouracil (MTU) because of their thynamide grouping act as antithyroid drugs inhibiting the organification of iodide, but do not alter the iodide transport. Their administration to an intact animal, therefore, might alter the thyroidal iodine kinetics. Here an attempt has been made to study the effect of MTU on thyroidal iodine kinetics in rats as well as to find out whether any difference in kinetics could be detected between different radioiodines, viz., 131I, 125I, and 123I. Cumulated thyroidal activity which is a time integral of the activity has been taken as the parameter to represent the sum effect of thyroidal iodine kinetics over a specific time period of interest. From the in vivo thyroidal activity measurements, carried out over extended periods of time, the cumulated activity was calculated for both MTU treated and normal rats that received 131I, 125I, or 123I at different times before the MTU start. Within a day of the start of the MTU there is a rapid loss of thyroidal iodine. The severity of the loss depended upon the time that elapsed between the start of the MTU schedule and the particular radioiodine administered. The absence of isotopic effect on the uptake as well as on the rate of uptake for the three different radioiodine isotopes studied has been brought out.
Administration, Oral↗
Effect of antithyroid agents 6-propyl-2-thiouracil and 1-mehtyl-2-mercaptoimidazole on human thyroid iodine peroxidase.
The mechanism of inhibition of human thyroid iodide peroxidase (TPO) by 6-propyl-2-thiouracil (PTU) and 1-methyl-2-mercaptoimidazole (MMI) used in the therapy of hyperthyroid patients was studied in vitro. The inhibition of TPO by MMI was not restored either by dialysis or by dilution, but the inhibition by PTU was restored by both treatments. PTU interacted directly with the product of TPO action (oxidized iodide) in the reaction mixture without significantly affecting TPO activity. MMI interacted directly with TPO and inhibited enzyme activity, rather than interacting with the product (oxidized iodide). The inhibition was irreversible with MMI, but reversible with PTU. The concentrations of PTU and MMI producing 50% inhibition of TPO were 2 x 10-6m and 8 x 10-7m, respectively, 2-Mercaptoimidazole inhibited TPO reversibly but 1-methylimidazole and imidazole did not. Both the methyl and mercaptoresidues in MMI moiety are thought to be essential to its irreversible inhibition of TPO. The in vivo effect of MMI and PTU on TPO activity was also studied. TPO activities in the thyroid homogenate of rats to which MMI (2 mg per rat) or PTU (10 mg per rat) had been administered intraperitoneally were determined before and after dialysis against buffer. TPO activity in the PTU treated thyroid homogenate was significantly lower than that in the control before dialysis, but the activity was restored to the control value after dialysis. On the contrary, TPO activity in the MMI treated thyroid homogenate was significantly lower than that in the control and was not affected by dialysis. These data may explain why MMI is a more potent inhibitor of iodination than PTU and may fit the clinical results observed when hyperthyroid patients are treated with these agents.
Animals↗