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PubMed1980

Correlation of plasma propylthiouracil levels with inhibition of thyroid hormone synthesis in the rat.

The inhibition of thyroid hormone synthesis was studied in relation to plasma levels of 6-n-propyl-2-thiouracil (PTU). Na 125I (5 muCi) was injected i.p. into adult male Sprague-Dawley rats. After 30 min, graded doses of PTU (0.2 mg/kg. 0.1 mg/kg, and 0.05 mg/kg) were similarly injected. Thyroid hormone synthesis was followed by the accumulation of radioactivity into thyroid glands, which were removed at specified time intervals. PTU levels were measured spectrophotometrically at the time of sacrifice. A-ditionally, PTU (35S) was used to confirm blood levels of PTU and also to follow intrathyroidal PTU levels. Plasma PTU levels in excess of 0.18 microgram/ml completely inhibited thyroid hormone synthesis. Levels between 0.14 and 0.09 microgram/ml had a partial effect, and PTU levels less than 0.09 microgram/ml had no effect on thyroid hormone synthesis.

Animals↗
PubMed1989

Phenolic and tyrosyl ring iodothyronine deiodination by the Caco-2 human colon carcinoma cell line.

Thyroid hormone metabolism was studied in the human Caco-2 colon carcinoma cell line, which at confluence exhibits several functions of differentiated enterocytes. Cells were harvested two to 17 days after reaching confluence. Intact cells and homogenates were tested for deiodination of [125I]-labeled substrates. Small amounts of thyroxine (T4) were converted by homogenates to 3,3',5'-triiodothyronine (rT3), 3,3'-diiodothyronine (3,3'-T2), and 1-, with no detectable production of 3,5,3'-triiodothyronine (T3) by homogenates or cells. rT3 was converted to 3,3'-T2 and 1- with an apparent Michaelis constant (Km) for rT3 of 24 nmol/L; 6-n-propyl-2-thiouracil (PTU) had a 50% inhibitory concentration of 30 nmol/L and abolished rT3 5'-deiodination at 1 mmol/L in the presence of 20 mmol/L dithiothreitol (DTT). T3 was deiodinated to 3,3'-T2 and 3'-monoiodothyronine (3'-T1) with an apparent Michaelis constant (Km) for T3 of 5.7 nmol/L; this reaction was not inhibited by 1 mmol/L PTU. Phenolic and tyrosyl ring deiodinating activities were maximal four and six days, respectively, after the cells reached confluence. Homogenates of cells grown in standard medium containing fetal calf serum had fivefold higher rT3 5'-deiodinating activity than cells grown in a serum-free defined culture medium, reflecting a fivefold difference in the apparent Vmax with no difference in the apparent Km for rT3. There was no difference in T3 5-deiodination rates in homogenates of Caco-2 cells grown in the two media until 12 days postconfluence, when cells grown in standard medium had higher activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma↗
PubMed1980

A metabolism chamber for measuring oxygen consumption in the laboratory rat and mouse.

Details are given for the construction and use of an inexpensive metabolism chamber to measure oxygen consumption in a relatively large group of laboratory rodents in a brief time. Metabolic rates (MR) were measured regularly in male and female Sprague Dawley rats, 11-114 days old, and mice, 100 days old. Adult mice had higher MR than rats of approximately the same age. Female rats and mice had higher MR than males at all times. To demonstrate the versatility of the metabolism chambers adult rats were injected once or for 9 consecutive days with 6-n-propyl-2-thiouracil (PTU) to inhibit thyroid function and reduce MR, or with the carboxymethylcellulose (CMC) vehicle. PTU failed to lower MR in the animals most probably because CMC vehicle tended to increase MR, an effect more prominent in males than females.

Age Factors↗
PubMed1983

Pituitary-thyroid activity and longevity in neonatally thyroxine-treated rats.

Wistar rats were made hypothyroidic by intraperitoneal thyroxine (T4) injection during the first 10 days of neonatal life. Levels of T4, 3,3',5-triiodothyronine (T3), thyroid-stimulating hormone (TSH) and prolactin in the blood of these rats were measured by radioimmunoassay. The T4 levels are about two-thirds of control values up to 20 months of age. T3 level is low only at a young age. TSH level shows no significant difference from control, but is about half that of control after the stimulation of secretion by 6-propyl-2-thiouracil. The level of prolactin is much higher in the T4-treated group than in controls. In male rats, life duration of hypothyroid rats was longer than control by about 4 months. The life extension effect of hypothyroidism was observed also in females, although the difference was smaller than that in males. The concentration of T4 in the blood of male rats is higher than females, and the decrease in T4 level by neonatal T4 treatment is also more marked in males.

Animals↗
PubMedDate not supplied

Influence of thyroid status on Ca2+ mobilization and amylase secretion in rat pancreatic acini.

Thyroid hormones influence Ca2+ homeostasis in both skeletal and cardiac muscle. Since secretory cells, like muscle cells, store and use Ca2+ in stimulus-response coupling, we have studied the effects of thyroid status on Ca2+ mobilization and secretion in a model secretory tissue, the pancreatic acinar cell. Hyperthyroidism was induced by rats by daily, subcutaneous injections of triiodothyronine for 8 days and hypothyroidism by adding 6-n-propyl-2-thiouracil to the drinking water for 14 days. Pancreatic acini were prepared by collagenase digestion of pancreatic tissue from hyper- and hypo-thyroid animals and from euthyroid controls. Ca2(+)-mobilization was assessed using Quin-2 fluorescence and secretion by assaying amylase release. The data indicate that the amount of Ca2+ mobilized by the muscarinic agonist carbachol or by cholecystokinin octapeptide increases with increasing thyroid hormone concentrations. Only in hypothyroidism was this change in Ca2+ homeostasis reflected by a parallel change in amylase secretion. This implies the existence of some compensatory mechanism which stabilizes secretory rate in the face of stimulus-evoked increases in intracellular Ca2+ concentration.

Aminoquinolines↗
PubMed1995

Occipital cortico-pyramidal projection in hypothyroid rats.

It is well established that the progressive disappearance of a transient occipito-spinal projection in neonatal rats involves the selective elimination of axonal collaterals. We studied whether the development of the occipito-spinal pathway was affected by hypothyroidism induced by treatment with the goitrogen 6n-propyl-2-thiouracil (PTU) beginning prenatally. Using both anterograde (biocytin and Dil) and retrograde (horseradish peroxidase and Fast Blue) tracing techniques in adult hypothyroid rats, we found that many cells with projections into the pyramidal tract are present in regions of visual cortex that are devoid of such cells in normal adult rats. Our results suggest that hypothyroidism induced by PTU treatment leads to the maintenance of occipito-spinal projections that are normally transient.

Animals↗
PubMed1996

Synthesis and interactions with thymidylate synthase of 2,4-dithio analogues of dUMP and 5-fluoro-dUMP.

The 2,4-dithio analogues of 2'-deoxyuridine and 2'-deoxy-5-fluorouridine have been synthesized by thiation of the previously described 2-thio analogues, and then phosphorylated enzymatically or chemically to yield 2,4-dithio-dUMP and 2,4-dithio-5-fluoro-dUMP. In striking contrast to the 2-thio and 4-thio analogues of dUMP, which are good substrates of thymidylate synthase, 2,4-dithio-dUMP is not a substrate. But, surprisingly, it is a competitive inhibitor, relative to dUMP, of the purified enzymes from both parental and FdUrd-resistant L1210 cells, with K(i) values of 32 microM and 55 microM, respectively. Although 2,4-dithio-5-fluoro-dUMP behaved as a typical slow-binding inhibitor of the enzyme, its K(i) value was 10(3)-10(4)-fold higher than those for the corresponding 2-thio and 4-thio congeners. Similarly, 2,4-dithio-FdUrd was a much weaker inhibitor of tumour cell growth (IC50 approximately 10(-5)M) than FdUrd (IC50 approximately 10(-9)M), 2-thio-FdUrd(IC50 approximately 10(-7)M) or 4-thio-FdUrd (IC50 approximately 5x10(-8)M), while with 2,4-dithio-dUrd no influence on cell growth could be observed. Theoretical considerations, based on calculated aromaticities of the uracil and thiouracil rings, suggest that lack of substrate activity of 2,4-dithio-dUMP may result from increased pyrimidine ring aromaticity of the latter, leading to resistance of C(6) to nucleophilic attack by the enzyme active center cysteine.

Animals↗
PubMed1985

On the coordination properties of Eu3+ bound to tRNA.

The luminescence properties of Eu3+ have been used to investigate the binding and coordination properties of the ion with tRNA, as an attempt to resolve the discussion of whether metal ions bind to tRNA in solution only by Debye-Hückel screening, or whether direct coordination to specific sites may occur. Binding studies with Escherichia coli tRNAmet/f (taking advantage of 4-thiouracil-sensitized Eu3+ emission) distinguish three classes of binding affinities. Two of these are single sites with affinities approx. 10(4) and approx. 10(3) tighter than the nonspecific affinity of Eu3+ for native DNA. Mg2+ competes for binding at both these sites. Measurement of the lifetime and excitation spectrum of Eu3+ bound to the highest affinity site shows that the ion has two to five non-phosphate ligands in its inner coordination sphere. The existence of this coordinated site demonstrates that electrostatic screening is not the only mechanism for metal ion interaction with tRNA. The coordination properties of the high-affinity Eu3+ site do not agree with the properties of any of the metal ion sites found in the two tRNAphe crystal forms. Possible reasons for this discrepancy are discussed; it may be that ions bind differently to isolated molecules in solution than to molecules packed in a crystal lattice.

Binding Sites↗
PubMed1996

Decreased growth rate and tumour formation of human anaplastic thyroid carcinoma cells transfected with a human thyrotropin receptor cDNA in NMRI nude mice treated with propylthiouracil.

The effect of the human TSH-receptor (TSHR) on the growth of human anaplastic thyroid carcinoma cells lacking the endogenous expression of TSHR, was studied both in vitro and in vivo in NMRI nude mice. Cells from a human anaplastic thyroid carcinoma cell line (C643) were transfected with a TSHR cDNA, and clones were isolated after neomycin selection. The expression of a functional receptor protein was ensured by analysis of the specific binding of 125I-TSH and measurement of TSH-induced cAMP. Incorporation of [3H]thymidine and increase in cell number was slightly inhibited by TSH in TSHR-expressing cells in vitro. In order to investigate whether the regained expression of a functional TSHR protein in C643 cells could influence the in vivo growth, cells were injected subcutaneously into NMRI nude mice. To manipulate the endogenous level of TSH, animals were given 6n-propyl-2-thiouracil (PTU; resulting in a high TSH level), T4 (a low TSH level) or no treatment (as a control). There seemed to be a TSH induced inhibition of tumour growth, since tumours in mice treated with PTU grew after a longer take rate and with a slower growth rate. The present results suggest a TSH-mediated growth inhibition in the TSHR-transfected C 643 anaplastic thyroid carcinoma cells.

Animals↗
PubMed1978

Regulation of thyroid hormone metabolism in rat liver fractions.

The nature of the conversion of thyroxine (T4) to triiodothyronine (T3) and reverse triiodothyronine (rT3) was investigated in rat liver homogenate and microsomes. A 6-fold rise of T3 and 2.5-fold rise of rT3 levels determined by specific radioimmunoassays was observed over 6 h after the addition of T4. An enzymic process is suggested that converts T4 to T3 and rT3. For T3 the optimal pH is 6 and for rT3, 9.5. The converting activity for both T3 and rT3 is temperature dependent and can be suppressed by heat, H2O2, merthiolate and by 5-propyl-2-thiouracil. rT3 and to a lesser degree iodide, were able to inhibit the production of T3 in a dose related fashion. Therefore the pH dependency, rT3 and iodide may regulate the availability of T3 or rT3 depending on the metabolic requirements of thyroid hormones.

Animals↗
PubMed1991

The derepression of enzymes of de novo pyrimidine biosynthesis pathway in Brevibacterium ammoniagenes producing uridine-5-monophosphate and uracil.

A mutant of Brevibacterium ammoniagenes producing large quantities of UMP and uracil is described. The mutations render bacteria braditrophic for arginine, sensitive to adenine, resistant to rifampicin and pyrimidine analogues 5-fluorouracil, 5-fluorouridine, azauracil and thiouracil. The activities of enzymes involved in the UMP biosynthesis, i.e. orotate phosphoribosyltransferase, orotate-5-monophosphate decarboxylase, dihydroorotate oxidase, are 4-, 3.5- and 4.5-fold higher in the mutant than in the parent strain when grown in minimal medium. The synthesis of these enzymes in mutant cells is not repressed in the presence of exogenous Ura. True revertants, which completely restore the wild-type phenotype, occur among the Arg+ clones. The nature of the mutation is discussed.

Brevibacterium↗
PubMed1991

Selective liquid chromatographic assay for propylthiouracil in plasma.

A liquid chromatographic assay was developed to quantitate propylthiouracil in plasma using an internal standard, 5-propyl-2-thiouracil, of similar structure and physical properties. Caffeine, which coelutes with propylthiouracil, was removed by extraction from serum treated with base. No other compounds were found to interfere in the assay. The drug was extracted from plasma with chloroform with a recovery of 59.4% and the intra- and inter-assay coefficients of variation were 5.7 and 3.3%, respectively. The assay was linear to 3 micrograms/ml with a lower detection limit of 40 ng/ml for a sample volume of 1 ml.

Caffeine↗
PubMed1990

Metabolism of aromatic and heterocyclic amine bladder carcinogens: bioanalytical considerations.

Aromatic and heterocyclic amines are environmental chemicals which can cause bladder cancer in man. Because these chemicals cause carcinomas at a site distal to their portals of entry, metabolic processes are involved in initiation of their carcinogenic effects. N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and its deformylated analogue, ANFT, were used as model compounds to assess metabolism. Electrochemical properties of ANFT made liquid chromatography with electrochemical detection a specific and sensitive method for analysis. Peroxidatic metabolism of ANFT by prostaglandin H synthase (PHS) in the presence of N-acetylcysteine resulted in the formation of 2-amino-4-(5-nitro-2-furyl)-5-(N-acetylcystein-S-yl)thiazole (ANFT-MA). This thioether product has an oxidation potential significantly lower than ANFT. Rat urinary excretion of ANFT-MA was significantly decreased with peroxidase inhibitors, 6-n-propyl-2-thiouracil and methimazole. Inhibitors did not alter excretion of ANFT or prostaglandin E2, a PHS product of arachidonic acid metabolism. 1H and 13C-NMR were selected to explore potential structural differences between ANFT and FANFT which might explain preferential PHS metabolism of ANFT. Evidence for a "zwitterion" configuration for ANFT but not FANFT was observed. ANFT in the "zwitterion" configuration would be a better reducing co-substrate. Chemical synthesis and GC-MS fragmentation patterns identified 3-(2,3-dihydro-1-methyl-2-pyrrolyl)pyridine as a peroxidatic product of nicotine metabolism. This peroxidatic product was found in urine from a cigarette smoker in an amount approximately 6% that observed for continine. Thus, a potential rôle for peroxidative metabolism was demonstrated in man.

Animals↗
PubMed1993

Determination of thiol-containing drugs by chemiluminescence-flow injection analysis.

A flow injection analysis procedure with chemiluminescence detection for the determination of both thiol-containing drugs and the amino acid cysteine is described. Procedures are based on the inhibition by the drugs of the chemiluminescence generated in the copper-catalysed oxidation of luminol by hydrogen peroxide. The proposed methods were applied to the determination of cysteine, N-acetylcysteine, penicillamine, 2-mercaptopropionylglycine and thiouracil in pharmaceuticals.

Acetylcysteine↗
PubMedDate not supplied

The inhibitory effect of testosterone on the development of metabolic tolerance to ethanol.

We have investigated the mechanism(s) of metabolic tolerance to ethanol in a rat strain (spontaneously hypertensive or SH) in which liver alcohol dehydrogenase (ADH) levels are very low due to a marked inhibitory effect of testosterone on ADH. Chronic ethanol administration resulted in marked increases in the rate of ethanol metabolism and in ADH activity (+65 to 90%). Oxygen consumption measured in the perfused livers of the ethanol-fed rats was also elevated (+40%). The administration of 6-n-propyl-2-thiouracil (PTU), which was previously found to reduce hepatic oxygen consumption and to increase ADH activity, resulted in no change in the rate of ethanol metabolism in the ethanol-fed rats and an increase in the sucrose-fed controls, suggesting that increased ADH activity is more important for the development of metabolic tolerance to ethanol, in the male SH rat, than increased oxygen consumption. The activity of the microsomal ethanol-oxidizing system (MEOS) in vitro was induced by chronic ethanol treatment (+95%), but it may only account for a small part (32%) of the increase in ethanol metabolism in vivo. Serum testosterone concentrations were lower in the ethanol-fed rats at peak blood ethanol levels, relative to those found in controls. Concurrent chronic administration of ethanol and testosterone abolished about one-third of the absolute increases in ethanol metabolism and in ADH activity in the ethanol-fed rats. In conclusion, most of the metabolic tolerance to ethanol, in the male SH rat, appears to occur mainly due to a testosterone-independent increase in ADH activity and to a lesser degree to an increase in ADH activity produced by a reduction in testosterone levels in the ethanol-fed rats.

Alcohol Oxidoreductases↗
PubMed1985

Superoxide anion is generated from cellular metabolites by solar radiation and its components.

Several endogenous cellular constituents were tested for their ability to produce superoxide anion (O2-) from ground-state molecular oxygen upon irradiation by solar radiation. The pyridine cofactors NADPH and NADH, riboflavin, and the nucleosides 2-thiouracil and 4-thiouridine were found to sensitize the transmission of photon energy from solar radiation and monochromatic radiation (290, 334, 365, and 405 nm) to oxygen, resulting in O2- formation, as detected by superoxide dismutase-inhibitable cytochrome c reduction. Quantum yields for the production of O2- indicate that NADPH is the most efficient and riboflavin the least efficient of the compounds tested. These data indicate that endogenous compounds may participate in the production of O2- by solar radiation and imply that O2- may play a role in sunlight-induced erythema and dermal carcinogenesis.

Anions↗
PubMed1988

99mTc-nitrido radiopharmaceuticals based on nitrogen heterocyclic ligands containing a thiol group.

The chromatographic and in vivo behaviour in mice of the 99mTcN- and 99mTc(Sn)-complexes of 2-mercaptopyridine, 2-mercaptopyrimidine, thiouracil, 6-mercaptopurine and thioguanine is compared. The biological distribution of the 99mTcN-complexes is generally different to that of the 99mTc(Sn)-complexes of the same ligand with the difference being very dependent on the structure of the ligand. The 99mTcN-mercaptopyrimidine complex has potential as a blood-cell labelling agent.

Animals↗
PubMed2005

Molecular insight into the effects of hypothyroidism on the developing cerebellum.

Despite the recognized importance of thyroid hormones for normal brain development, little is known about the critical molecular events underlying this role. We investigated the molecular basis of thyroid hormone action on the developing brain by comparing genome-wide gene expression patterns in the cerebellum between euthyroid and hypothyroid juvenile mice using microarrays. Pregnant dams were treated with 0.1% or 0.04% 6-propyl-2-thiouracil (PTU) in drinking water continuously from day 13 post conception until weaning to produce hypothyroid pups. Cerebella were collected from vehicle and 0.1% PTU treated pups at post-natal day (PND) 15, and mRNA from these was subjected to microarray analysis using Agilent high-density oligonucleotide chips. Statistical analysis (MAANOVA) revealed significant differential expression in 2940 genes including 1357 up- and 1583 down-regulated genes. Further analysis (combined MAANOVA and ANOVA) identified 204 significantly altered genes. Hypothyroidism had a greater effect on gene expression in male than in female pups. Transcriptional changes in several genes [Syt12 (Synaptotagmin 12), Rcor (RE1-silencing transcription factor co-repressor), Bag3 (Bcl-associated athanogene 3), p21, cyclin D, Bax (Bcl2-associated X protein), and Pcp2 (Purkinje cell protein 2)] were confirmed using real-time (RT) PCR analysis. Significantly altered expression of Bag3 in cerebella from PND 15 and PND 60 pups exposed to PTU suggests permanent functional alterations in the hypothyroid brain. The thyroid hormone negative regulation of Rcor expression was confirmed in vitro using HepG2 cells. In addition to Rcor, expression of several other genes that code for critical components of the REST (RE1-silencing transcription factor) pathway was shown to be altered in hypothyroid animals. These results suggest that modification of this pathway may have a significant role in causing impaired development in the hypothyroid brain.

Animals↗