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PubMed1977

Effect of anti-thyroid agents, methimazole and propylthiouracil, on brain noradrenaline content.

1 Methimazole (1-methyl-2-mercaptoimidazole, MMI) and propylthiouracil (6-propyl-2-thiouracil, PTU) which are used in the therapy of hyperthyroidism were found to reduce brain noradrenaline (NA) content. Endogenous NA levels in rat brain were reduced from 1 to 6 h after intraperitoneal injection of MMI by doses in excess of 25 mg/kg and by PTU at a dose of 50 mg/kg. However, endogenous NA in the rat heart was only slightly reduced after 50 mg/kg of MMI, and was not affected by PTU (50 mg/kg). 2 Both MMI and PTU effectively inhibited the in vivo conversion of [3H]-dopamine into [3H]-noradrenaline ([3H]-NA) in the brain of rats after a single intraperitoneal injection of doses above 10 mg/kg (MMI) and 25 mg/kg (PTU). This inhibition by MMI and PTU was dose-dependent over the range of 10 mg/kg to 50 mg/kg, was highest after 2-3 h and continued for at least 6 h after their injection; The conversion rates returned to normal after 24 hours. 3 The results suggest that the reduction of brain NA by these drugs is, at least in part, due to the inhibition of brain dopamine beta-hydroxylase.

Animals↗
PubMedDate not supplied

Neutron capture therapy research in Australia.

Neutron capture therapy research in Australia has continued to grow since the first Australia-Japan workshop in April, 1986. The support base has broadened and the wide range of contributing laboratories includes universities, research institutes, and hospitals. Considerable progress has been made in boron chemistry--an accurate boron assay technique has been developed, boron analogues of chlorpromazine and thiouracil have been synthesised or nearly so, and decaborane conjugation with monoclonal antibodies has been achieved to the required loadings. In vitro cell survival experiments are proceeding in the Moata reactor using human melanoma and mouse cell lines incubated with enriched boronophenylalanine and boron tetraphenyl porphyrins. Electron microscopy examination of radiation damaged morphology shows considerable differences between cell lines. Progress with the nude mouse human melanoma model has been slow because of the lack of a reliable in vivo melanotic melanoma line, and the B16 mouse line is found to be more efficacious. Tailored beam calculations for the 10 MW HIFAR reactor indicate the difficulty of obtaining a suitable therapeutic beam because of the generated gamma dose in the beam filters. A new approach to NCT utilises the enormous cross section of 157Gd and the induced-Auger effect which has been shown to cause double strand breaks in circular DNA.

Animals↗
PubMed1993

Thyroxine 5'-deiodinase type II activity in chick pineal and Harderian gland: nyctohemeral rhythmicity and its regulation by noradrenergic input.

Circadian rhythmicity of type II thyroxine 5'-deiodinase (5'-D) activity was studied in the pineal gland and Harderian glands of chicks. Only Harderian 5'-D activity showed a nyctohemeral rhythmicity with a maximal peak during the day time (1300), while no rhythm of enzyme activity was found in the pineal gland. Besides type II 5'-D activity, we found high basal levels of the type I isoenzyme in both glands; this activity was specifically suppressed by the addition of 6-n-propyl-thiouracil (PTU). However, day-night differences in Harderian 5'-D activity were maintained even after the addition of PTU. This activity was not affected for either continuous light exposure or darkness during the day. 5'-D activity seems to be regulated by the noradrenergic input, since the enzymatic activity was stimulated by a beta-adrenergic agonist, isoproterenol, and by the alpha-adrenergic agonist, phenylephrine, in both pineal and Harderian glands. Both drugs affected 5'-D activity in the Harderian gland by stimulating the enzyme activity over basal levels.

Animals↗
PubMed1998

Electrophysiological responses to bitter stimuli in primate cortex.

Studies investigating fine details of gustatory coding in the domain of each basic taste quality have been completed for sweet, salt, and sour stimuli. In the present experiment, we used chemicals that humans describe as predominantly bitter. We recorded the activity of 50 taste neurons in insular cortex of two cynomolgus macaques. Stimuli were water, fruit juice, glucose, NaCl, HCl, and 16 bitter solutions. In a multidimensional taste space the 16 bitter stimuli formed a coherent cluster composed of three main subgroups: (1) QHCl, phenylalanine, theophylline, caffeine, propyl-thiouracil (PROP), and phenylthiocarbamide (PTC), all of which humans describe as rather purely bitter, (2) MgCl2, CaCl2, NH4Cl, and arginine, which humans describe as salty-bitter, and (3) urea, cysteine, and vitamin B1, which are described as sour-bitter. Vitamin B2, histidine and nicotine were in the center of the bitter cluster. Human descriptions of taste qualities conformed well to the presumed quality of each stimulus as inferred from its position in the multidimensional space (MDS), reinforcing the use of the macaque as a neural model for human gustation.

Animals↗
PubMed1992

Photooxidation products of merocyanine 540 formed under preactivation conditions for tumor therapy.

In order to gain insight into the preactivation of merocyanine 540 (MC540) 1 for the photodynamic therapy (Gulliya et al., 1990a, Photochem. Photobiol. 52, 831-838) its photo-oxidation was investigated. After irradiation of MC540 1 on a preparative scale three main photodegradation products were isolated with 16-20% yields. They turned out to be derivatives of benzoxazole, thiouracil and thiohydantoin with the structures 4, 5 and 6, respectively. It may be possible that they contribute to the cytostatic and antiviral activity of preactivated MC540 1.

Humans↗
PubMed1977

The effect of age and thyroid hormones upon the ability of the chick heart to deaminate monoamines.

The effect of age and thyroid hormones upon the ability of chick heart homogenates to metabolize monoamines has been investigated. 5-Hydroxytryptamine is entirely metabolized by a monoamine oxidase (MAO) with the characteristics of MAO-A, whereas some of the tyramine and all of the benzylamine are oxidatively deaminated by a clorgyline-resistant, but semicarbazide-sensitive enzyme, with a similar subcellular distribution to that of MAO. The remainder of the tyramine deamination is brought about by MAO-A and MAO-B. The specific activities of both clorgyline-sensitive and resistant enzymes are increased by the same proportion by increase in age or by treatment with (--)-thyroxine, and decreased by 2-thiouracil. The significance of these results is discussed.

Animals↗
PubMed1979

Selective influences of age and thyroid hormones on type A monoamine oxidase of the rat heart.

The specific actiivty of rat heart MAO, towards both tyramine and benzylamine as substrates, was found to increase with the age of the animal, and also after administration of (-)-thyroxine to young male rats. Conversely, enzyme activity was decreased in animals made hypothyroid by including 2-thiouracil in their diet. However, with both age and altered thyroid status, relatively greater changes in the deamination of tyramine rather than in that of benzylamine, were obtained. Clorgyline and deprenyl, used as inhibitors of rat heart MAO, indicated that tyramine is metabolized solely by MAO-A, whereas benzylamine is a substrate for both MAO-A and -B, and also a clorgyline- and deprenyl-resistant enzymic activity. The proportional contribution of MAO-A, -B and the clorgyline-resistant enzyme towards the total benzylamine deamination in the rat heart was found to vary with the age and with altered thyroid status of the animal in such a way that selective changes in the activity of MAO-A appear to be largely responsible for the overall changes in the specific activity of rat heart MAO which occur in response to these developmental factors.

Aging↗
PubMed1987

Effects of glucagon on cAMP accumulation and ketogenesis in hepatocytes from euthyroid and hypothyroid rats.

The resistance to the effects of glucagon was studied in isolated hepatocytes prepared from male rats treated with 6N-propyl-2-thiouracil (PTU). Incorporation of [14C]oleate into ketone bodies in response to various concentrations of glucagon (10(-5) to 10(-10) M) was reduced in hepatocytes from hypothyroid rats compared with the euthyroid group. The reduced sensitivity to the effects of glucagon on ketogenesis after treatment with PTU was associated with a reduced ability of those hepatocytes to maintain cyclic adenosine-3',5'-monophosphate (cAMP) at levels required to stimulate ketogenesis. The concentration of cAMP in response to glucagon (10(-5) to 10(-10) M) was diminished in hepatocytes from hypothyroid rats, compared with those from euthyroid animals.

Animals↗
PubMed1972

Deiodination of thyroid hormones by the perfused rat liver.

1. An investigation has been made into the deiodination of thyroid hormones by the perfused rat liver. The hormones were labelled with (125)I in the phenolic ring and the rate of deiodination was estimated by measuring the release of radio-iodide into the perfusate.2. At tracer concentrations, 0.98% of the liver thyroxine is deiodinated/5 min. The deiodination of tri-iodothyronine is considerably faster, 3.3%/5 min.3. Deiodination is very sensitive to changes in temperature.4. The reaction shows saturation kinetics typical of many enzymes, the reciprocal of the rate of deiodination being proportional to the reciprocal of the hormone concentration in the tissue. The maximum rate of deiodination of each hormone is about 1.5 mug/min for a whole liver preparation weighing 16 g.5. Tri-iodothyronine inhibits thyroxine deiodination and vice versa, suggesting that a single enzyme is responsible for both reactions.6. Propyl thiouracil (PTU) at high concentrations inhibits the deiodination of both hormones.7. An abnormally high rate of deiodination is associated with the actual injection of hormone into the preparation. This suggests that only the free (unbound) hormone in the tissue is directly available to the deiodinating enzyme.8. About half of the whole body deiodination of thyroxine is relatively insensitive to PTU. It is suggested that most of this type of deiodination is performed in the liver and that the process is one of inactivation.

Animals↗
PubMed1975

Thyroid control of small intestinal oxygen consumption and the influence of sodium ions, oxyhen tension, glucose and anaesthesia.

1. Oxygen consumption of jejunum removed from either killed or anaesthetized euthytoid, hypothyroid and triiodothyronine (T3)-treated rats was measured polarographically in vitro. 2. Hypothyroidism induced by drinking 6-n-propyl-2-thiouracil depressed jejunal oxygen consumption. 3. Treatment of euthyroid rats with T3 stimulated jejunal oxygen consumption by 39% in the presence of 28 mM glucose and by 23% in its absence. 4. Sodium ions appear to play a major permissive role in the action of T3 on jejunal oxygen uptake. In the presence of sodium, T3 stimulated significantly the oxygen consumption by 23% while in the absence of sodium the stimulation was only 10% which was not significant. The sodium-sensitive oxygen uptake of the jejunum was expanded by 57% after T3 treatment.

Anesthesia, General↗
PubMed1970

Cretinism in rats: enduring behavioral deficit induced by tricyanoaminopropene.

Rats reared on diets containing tricyanoaminopropene, the antithyroid compound that stimulates RNA synthesis, showed a deficit in performance on automated closed-field maze tests many weeks after discontinuation of the drug. The rats were also tested while still receiving the drug, and performance deficits were indicated in tests of Y-maze reversal and manual closed-field maze performance; rats treated with the drug and with thiouracil behaved in a highly similar fashion on several tasks. No evidence of facilitation by tricyanoaminopropene appeared in any of the eight learning situations used. Exposure to tricyanoaminopropene before and after birth, at doses sufficient to produce anatomical cretinism, apparently induces an enduring behavioral deficit which is similar to that of neonatal thyroidectomy-induced cretinism in rats and which parallels the mental retardation associated with human cretinism.

Amines↗
PubMed1995

Differential activities of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains.

A series of 23 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives that were highly potent inhibitors of wild-type human immunodeficiency virus type 1 strain IIIB (HIV-1/IIIB) replication in CEM cells were evaluated against a panel of HIV-1 mutant strains containing the replacement of leucine by isoleucine at position 100 (100-Leu-->Ile), 103-Lys-->Asn, 106-Val-->Ala, 138-Glu-->Lys, 181-Tyr-->Cys, 181-Tyr-->Ile, or 188-Tyr-->His in their reverse transcriptase (RT). A different structure-antiviral activity relationship was found, depending on the nature of the mutated amino acid in the HIV-1 RT. The results show that 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil, 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylphenylthio)uracil, and 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylphenylthio)-2-thiouracil remain active against the majority of viruses containing single mutations which confer resistance to nonnucleoside RT inhibitors.

Antiviral Agents↗
PubMed1981

Factors affecting phaeomelanin production by a melanin-producing (mel) mutant of Vibrio cholerae.

In a previous study we isolated melanin-producing (mel) mutants of Vibrio cholerae and demonstrated that production of melanin during growth on solid media was stimulated by L-tyrosine and L-cysteine. In the studies reported here we analyzed factors that affected melanin production in liquid media and determined the abilities of radioactively labeled amino acids to serve as precursors for the formation of melanin by V. cholerae. Radioactivity from L-cysteine and from L-tyrosine was preferentially incorporated into partially purified melanin, providing further evidence for production of phaeomelanin by V. cholerae. Cuprous ions stimulated production of melanin by V. cholerae in defined liquid medium, but melanin formation was inhibited by high concentrations of L-cysteine or thiouracil. The inhibition of melanin formation by sulfhydryl compounds is most likely due to their ability to bind copper ions that are essential for tyrosinase activity.

Copper↗
PubMed1969

Sulfur-deficient transfer ribonucleic acid in a cysteine-requiring, "relaxed" mutant of Escherichia coli.

A cysteine-requiring mutant of the parent strain Escherichia coli Hfr Cavalli (RC(rel), Met(-), lambda) has been isolated. The mutant was selected by using replica plating after mutagenesis by N-methyl-N'-nitro-N-nitrosoguanidine. The mutation appears to be in the gene for sulfite reductase, since the mutant could utilize sulfide but not sulfite as a sulfur source. The mutant was found to be RC(rel) with respect to both methionine and cysteine. During cysteine starvation, transfer ribonucleic acid (tRNA) deficient in 4-thiouracil was produced, and in vivo studies indicate that this tRNA can accept sulfur groups to a greater extent than normal tRNA. Further, there were differences both in the rate and extent of amino acid acceptance between normal and sulfur-deficient tRNA. This suggests that thionucleotides are involved in at least one of the biological functions of the tRNA molecule.

Amino Acids↗
PubMed1961

Utilization of sulfur compounds by Streptococcus bovis.

Prescott, J. M. (A. &. M. College of Texas, College Station). Utilization of sulfur compounds by Streptococcus bovis. J. Bacteriol. 82:724-728. 1961.-Two strains of Streptococcus bovis utilize a variety of compounds as their only source of sulfur, yet exert a definite selectivity in their nutritional requirements for this element. Among sulfur-containing amino acids and related compounds, cystine and cysteine support excellent growth, but cysteic acid and cysteine sulfinic acid do not; methionine is completely inactive as an only sulfur source, but growth is provided by lanthionine, djenkolic acid, allo-cystathionine, homocystine, homocysteine, and glutathione. Several organic sulfur compounds other than amino acids are effective sulfur sources, among which are thioglycolate, thiomalate, thiourea, and thiouracil. In contrast, thiodiglycolate, thiodiglycol, and (phenylthio) acetic acid fail to support growth. Of the inorganic sulfur sources tested, sulfide and thiosulfate are utilized, but sulfite and sulfate are not; it thus appears that the state of oxidation is a critical factor in the utilization of sulfur by these strains of S. bovis. A complex amino acid mixture, without sulfur-containing amino acids, produces more rapid and reproducible growth than either arginine or ammonium acetate when used as a nitrogen source for testing the sulfur compounds. Growth rates are frequently better when the sulfur sources are autoclaved than when they are sterilized by filtration, although the qualitative responses to the compounds are generally similar.

Alanine↗
PubMed1961

Survey of fourteen metabolic inhibitors for their effect on endospore germination in Bacillus subtilis.

Curran, Harold R. (U. S. Department of Agriculture, Washington, D. C.) and Georges Knaysi. Survey of fourteen metabolic inhibitors for their effect on endospore germination in Bacillus subtilis. J. Bacteriol. 82:793-797. 1961.-Phase contrast microscopy was used to study the effects of metabolic antagonists upon incipient spore germination in glucose agar-film microcultures. The period of observation was 1 to 2 hr. Of 14 compounds tested, only ethanol in 10% concentration (v/v) caused almost complete inhibition. Oxamic acid and dl-ethionine were slightly stimulatory; 6-methyl thiouracil and octyl aldehyde were without effect. The inhibiting effect of the remainder depended upon the concentration of the antagonist. The stimulating effect of glucose on germination is discussed.

Antimetabolites↗
PubMed2000

Template nucleotide moieties required for de novo initiation of RNA synthesis by a recombinant viral RNA-dependent RNA polymerase.

The recombinant RNA-dependent RNA polymerase of the bovine viral diarrhea virus specifically requires a cytidylate at the 3' end for the de novo initiation of RNA synthesis (C. C. Kao, A. M. Del Vecchio, and W. Zhong, Virology 253:1-7, 1999). Using RNAs containing nucleotide analogs, we found that the N3 and C4-amino group at the initiation cytidine were required for RNA synthesis. However, the ribose C2'-hydroxyl of the initiating cytidylate can accept several modifications and retain the ability to direct synthesis. The only unacceptable modification is a protonated C2'-amino group. Quite strikingly, the recognition of the functional groups for the initiation cytidylate and other template nucleotides are different. For example, a C5-methyl group in cytidine can direct RNA synthesis at all template positions except at the initiation cytidylate and C2'-amino modifications are tolerated better after the +11 position. When a 4-thiouracil (4sU) base analog that allows only imperfect base pairing with the nascent RNA is placed at different positions in the template, the efficiency of synthesis is correlated with the calculated stability of the template-nascent RNA duplex adjacent to the position of the 4sU. These results define the requirements for the specific interactions required for the initiation of RNA synthesis and will be compared to the mechanisms of initiation by other RNA-dependent and DNA-dependent RNA polymerases.

Animals↗
PubMed1998

A highly selective, high-affinity transporter for uracil in Trypanosoma brucei brucei: evidence for proton-dependent transport.

The presence of an uptake mechanism for uracil in procyclic forms of the protozoan parasite Trypanosoma brucei brucei was investigated. Uptake of [3H]uracil at 22 degrees C was rapid and saturable and appeared to be mediated by a single high-affinity transporter, designated U1, with an apparent Km of 0.46 +/- 0.09 microM and a Vmax of 0.65 +/- 0.08 pmol x (10(7) cells)(-1) x s(-1). [3H]Uracil uptake was not inhibited by a broad range of purine and pyrimidine nucleosides and nucleobases (concentrations up to 1 mM), with the exception of uridine, which acted as an apparent weak inhibitor (Ki value of 48 +/- 15 microM). Similarly, most chemical analogues of uracil, such as 5-chlorouracil, 3-deazauracil, and 2-thiouracil, had little or no affinity for the U1 carrier. Only 5-fluorouracil was found to be a relatively potent inhibitor of uracil uptake (Ki = 3.2 +/- 0.4 microM). Transport of uracil was independent of extracellular sodium and potassium gradients, as replacement of NaCl in the assay buffer by N-methyl-D-glucamine, KCl, LiCl, CsCl, or RbCl did not affect initial rates of transport. However, the proton ionophore carbonyl cyanide chlorophenylhydrazone inhibited up to 70% of [3H]uracil flux. These data show that uracil uptake in T. b. brucei procyclics is mediated by a single high-affinity transporter with high substrate selectivity and are consistent with a nucleobase-H+-symporter model for this carrier.

Animals↗