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PubMed1997

Gas chromatographic determination of residues of thyreostatic drugs in bovine muscle tissue using combined resin mediated methylation and extraction.

A method is described for the assay of residues of the thyreostatic substances 2-thiouracil, 6-methyl-2-thiouracil, 5- and 6-propyl-2-thiouracils and 6-phenyl-2-thiouracil in beef muscle at levels of quantitation down to 25 microg/kg for thiouracil and 15 microg/kg for substituted thiouracils. Analytes are extracted from the muscle matrix with acetonitrile and methylated by absorption onto a macroporous anion exchange resin followed by treatment with methyl iodide in acetonitrile at room temperature. Supercritical carbon dioxide is also a suitable derivatization solvent. Determination is carried out using gas chromatography with mass spectrometric detection. The methyl ester of 2,4,5-trichlorophenoxyacetic acid serves as an internal standard while 5-methyl-2-thiouracil is a suitable surrogate. 5-Ethyl-2-thiouracil is added to minimise losses of the analytes during the analysis. The method exhibits a linear range of 25-625 microg/kg for the substituted thiouracils and 50-1250 microg/kg for 2-thiouracil. Recovery of the analytes ranges from 50% for 6-phenyl-2-thiouracil to 90% for 2-thiouracil with coefficients of variation of less than 10%.

Animals↗
PubMed1981

Dependency of maximum goitrogenic response on some minimal level of thyroid hormone production.

Thyroidal activity was studied in chicks given dietary thiouracil in conjunction with daily doses of thyroxine and with diets adequate and deficient in iodine. DL-thyroxine administered at doses up to 1.0 microgram per day for 10 to 12 days had no effect or slightly increased thyroid weight. Both the epithelial and colloid components of the thyroid gland were increased in response to thiouracil and to thiouracil in combination with low dosages of exogenous thyroxine. Radioiodine uptake was increased above the control with thiouracil and with thiouracil in conjunction with .5 and 1.0 microgram DL-thyroxine given daily. Birds receiving thiouracil, with and without exogenous thyroxine, showed a different pattern of radioiodine uptake and release than the control birds. Thiouracil-treated birds showed a rapid uptake of iodine following its administration, which was followed by a rapid decline immediately after peak accumulation, whereas in control birds thyroidal radioiodine concentration reached a plateau at the maximum concentration attained. The goitrogenic response to thiouracil was much greater when the diet was supplemented with iodine than when the diet was iodine-deficient. Thyroids under iodine deficiency contained greater percentages of epithelial tissue than with iodine-supplemented diets. Thyroid glands of chicks given thiouracil in an iodine-supplemented diet contained much more colloid than glands from iodine-deficient chicks with or without thiouracil. DL-thyroxine at a dosage of .5 microgram per day to chicks given thiouracil in an iodine-adequate diet increased, whereas higher dosages decreased thyroidal colloid. It is concluded that some minimal concentration of thyroid hormone is required for maximum goitrogenic response. It is not clear whether the response is entirely due to an effect on thyrotropin production or whether there is an effect of thyroid hormone on the thyroid gland itself.

Animal Feed↗
PubMed1975

Interrelationships between athyroetic and copper-deficient states in rats.

Possible interrelationships of copper-deficient (copper-deficient ration) and hypothyroid (thiouracil treatment) states in rats were examined. Clinical signs, necropsy changes, and thyroxine concentrations were determined in 6 groups of rats treated as follows: group A--nontreated control; group B--thiouracil treated; group C--fed copper-deficient ration; group D--thiouracil treated and fed copper-deficient ration; group E--thyroid-stimulating hormone (TSH) treated; and group F--TSH treated and fed copper-deficient ration. Clinical signs occurred first and were most severe in the thiouracil-treated rats fed copper-deficient ration and included conformational changes and slower maturation, weakening of ear cartilage, middle ear changes (reflected by tilting of heads), and alopecia. Fatty infiltration of hepatic tissue was found in all rats fed copper-deficient rations, and considerable fluid retention occurred in rats fed copper-deficient ration and subjected to daily TSH treatment. Adrenal gland weights were 81% of control values (adjusted for body weight) in thiouracil-treated rats fed copper-deficient ration, and hypophysis weights were 114 and 154% of control values in thiouracil-treated rats and thiouracil-treated rats fed copper-deficient ration, respectively. Thyroid gland weights were 281% of control values in both thiouracil-treated rats and thiouracil-treated rats fed copper-deficient ration. Plasma thyroxine concentrations were markedly reduced (9% of control value) in thiouracil-treated rats fed copper-deficient ration. Thus, copper-deficient and hypothyroid states were considerably enhanced when the 2 existed concurrently, giving added meaning and necessity to close surveillance of trace mineral concentrations and thyroid gland status.

Adipose Tissue↗
PubMed2000

Positron emission tomography of experimental melanoma with.

Positron emission tomography (PET) has evolved as a new diagnostic modality in cancer patients. Thioureylenes, such as thiouracil and methimazole, are known to be incorporated into growing melanin and selectively retained in melanotic melanoma. In the present study we used [(76)Br]5-bromo-2-thiouracil as tracer for PET imaging of human and murine melanotic melanoma transplanted subcutaneously into rats. The melanomas were clearly depicted 1 day after the injection, when [(76)Br]5-bromo-2-thiouracil was retained in the tumors though the overall radioactivity concentration in the body had declined. Accumulation of (76)Br was also seen in bladder, liver, and kidney. In addition, the rats were simultaneously injected with [(125)I]5-iodo-2-thiouracil and the tissue distribution of radioactivity was mapped by whole-body autoradiography. The results confirmed the selective uptake of thiouracil in the melanoma where the concentration of (125)I-radioactivity was about three-fold higher than that in the liver and lungs. These results show the possibility of using [(76)Br]5-bromo-2-thiouracil for PET diagnostics of melanoma, including dosimetry, prior to targeted therapy using [(131)I]5-iodo-2-thiouracil or [(211)At]5-astato-2-thiouracil.

Animals↗
PubMed1992

Changes in liver concentration of N-acetylglutamate and ornithine are involved in regulating urea synthesis in rats treated with thyroid hormone.

The purpose of this study was to elucidate the mechanism by which thyroid hormone alters urea synthesis. A set of three experiments was investigated in three groups of rats given 6-propyl-2-thiouracil (a thyroid inhibitor) without triiodothyronine treatment, treated with 6-propyl-2-thiouracil plus triiodothyronine or neither 6-propyl-2-thiouracil nor triiodothyronine (control). We attempted to determine whether the concentration of ornithine and N-acetylglutamate regulated urea synthesis and whether activities of two ornithine-catabolizing enzymes accounted for changes in ornithine concentration. Urinary excretion of urea and the liver concentration of N-acetylglutamate and ornithine in rats given 6-propyl-2-thiouracil plus triiodothyronine were significantly lower than in rats given 6-propyl-2-thiouracil alone. The liver concentration of N-acetylglutamate was correlated to urea excretion (r = 0.911, P less than 0.001). The activities of carbamylphosphate, synthetase, ornithine aminotransferase and ornithine decarboxylase in liver of the group treated with 6-propyl-2-thiouracil alone were significantly lower than those of the 6-propyl-2-thiouracil plus triiodothyronine-treated group. The results suggest that a higher liver concentration of N-acetylglutamate and ornithine in the hypothyroid (6-propyl-2-thiouracil only) rats is likely to stimulate urea synthesis. The thyroid hormone-induced increase in activities of ornithine catabolizing enzymes may be primarily responsible for changes in ornithine concentration.

Animals↗
PubMed1986

Iodothiouracil as a melanoma localizing agent.

Thiouracil and various derivatives are selectively incorporated into the melanin pigment of melanomas during biosynthesis by serving as false melanin precursors. Using the transplantable Harding-Passey melanoma carried in BALB/c mice, we have extended our previous studies with sulfur-35 (35S) thiouracil. The persistence of high levels of [35S]thiouracil in tumor for periods of up to 2 wk has been demonstrated; during this time the drug content in normal tissues returned to near background levels. The variety of iodine isotopes available makes iodothiouracil a particularly promising melanoma-localizing agent. Tumor uptake and biodistribution of [35S]thiouracil and iodothiouracil (both iodine-127 (127I) and iodine-125 (125I) labeled) have been compared and were found to be essentially the same. The selectivity of [125I]thiouracil for melanoma has been qualitatively demonstrated by autoradiography of whole-body sections and quantitated by analysis of tumor and selected tissues. Iodothiouracil was also shown to localize in remote secondary metastases using a metastatic variant of the Harding-Passey melanoma currently being developed in our laboratory. These studies confirm the melanoma localizing capabilities of an iodinated thiouracil, and therefore the potential of using iodinated thiouracil derivatives for diagnosis and therapy of melanotic melanomas.

Animals↗
PubMed2004

Association of Cu2+ with uracil and its thio derivatives: a theoretical study.

The structures and relative stabilities of the complexes between Cu2+ and uracil, 2-thiouracil, 4-thiouracil, and 2,4-dithiouracil were investigated by B3LYP/6-311+G(2df,2p)//B3LYP/6-31G* DFT calculations. In those systems in which both types of basic centers, that is, a carbonyl and a thiocarbonyl group, are present, association of Cu2+ with the oxygen atom is systematically favored, in contrast to what was found for the corresponding Cu+ complexes. This can be understood by considering that association of Cu2+ is immediately followed by oxidation of the base, which accumulates the negative charge at the oxygen atoms. Similarly, for 2,4-dithiouracil the most basic site for Cu+ attachment is the sulfur atom at the 4-position, while for association of Cu2+ it is sulfur at the 2-position. In contrast, differences between uracil-Cu+ and uracil-Cu2+ complexes are very small, and in both cases the oxygen atom at the 4-position is the most basic. Cu2+ binding energies are about 4 and 1.2 times larger than Cu+ binding energies and proton affinities, respectively. Uracil- and thiouracil-Cu2+ complexes are thermodynamically unstable but kinetically stable with respect to their dissociation into uracil*+ + Cu+ or thiouracil*+ + Cu+. The Cu2+ binding energies vary with the difference between the second ionization potential of the metal and the first ionization potential of the base. regardless of the reference acid (H+, Cu+, Cu2+) the basicity trend is 2,4-dithiouracil > 4-thiouracil > 2-thiouracil > uracil.

Cations↗
PubMed1988

The binding of thioureylene compounds to human serum albumin.

The binding interactions of some thioureylene compounds to human serum albumin were studied in vitro by ultraviolet spectroscopy and equilibrium dialysis. Binding of 6-n-propyl-2-thiouracil, 6-n-benzyl-2-thiouracil and 2-thiouracil to human serum albumin results in a red shift of the ultraviolet absorption maximum, suggesting that the binding site is a hydrophobic area of the protein. Bindings of 6-n-propyl-2-thiouracil and 6-n-benzyl-2-thiouracil to human serum albumin are characterized by two classes of sites while 6-n-propyl-uracil and 2-thiouracil bind to one low-affinity binding site. In addition, an identification of those sites was performed by measuring the displacement of these drugs. The data show that the moderate-affinity site is common with the warfarin site while the low-affinity site is likely to be shared by benzodiazepines. It is concluded that the binding is enhanced by the hydrophobicity of the substituent in the thioureylene compounds, and it is further shown that thiol-group substitutions in the thioureylene ring will weaken the binding.

Antithyroid Agents↗