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PubMed1975

Comparison of radiolysis products of thymine and thymidine with e.s.r. results.

Radicals determined by e.s.r. spectrometry of irradiated thymine or thymidine and radiolytic products generated under tha ction of gamma rays in aerated aqueous solutions have been compared. This comparison lies mainly in the fact that a radical R gives rapidly the corresponding peroxide ROOH. The authors have isolated and characterized twenty peroxides, i.e., the four isomers cis (-), cis (+), trans (-), trans(+) of 6-hydroperoxy-5-hydroxy-5,6-dihydrothymidine; the four isomers cis (-), cis (+), trans (-), trans (+) of 5-hydroperoxy-6-hydroxy-5,6-dihydrothymidine; 5-hydroperoxy-2-deoxyuridin;cis and trans 6-hydroperoxy-5-hydroxy-5,6-dihydrothymine; cis and trans 5-hydroperoxy-6-hydroxy-5,6-dihydrothymine; 5-hydroperoxymethyl-uracil; 5-hydroperoxy-5,6-dihydrothymine;cis and trans 6-hydroperoxy-5,6-dihydrothymine; 5-hydroperoxy-5-methyl barbituric acid; 5-hydroperoxy-5-methyl hydantoin; trans 5,6-dihydroperoxy-5,6-dihydrothymine. Most of thethymine and thymidine radicals hypothesized or described in the literature were correlated to these peroxides. However, the presence of certain peroxides could not be explained by recognized radicals. Taking advantage of this fact, the existence of new thymine or thymidine radicals so far unknown can be predicted.

Chromatography, Thin Layer↗

PubMed2004

Opposite effects of depressant and convulsant barbiturate stereoisomers on acetylcholine release from the rat hippocampus in vivo.

BACKGROUND: It has been shown that the R(-) isomer of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) induces loss of the righting reflex (LRR), while S(+)-MPPB causes pure excitatory effects, including convulsions, in vivo. METHODS: We studied the effects of the depressant and convulsant MPPB stereoisomers on rat hippocampal acetylcholine (ACh) release in vivo, using a brain microdialysis technique in freely moving animals. RESULTS: R(-)-MPPB 60 and 90 mg x kg(-1) i.p. decreased ACh release from the rat hippocampus by 44.1 (8.2)% and 60.8 (8.2)%, respectively. In the hippocampus, the local application of bicuculline, a gamma-aminobutyric acid (GABA)(A) receptor antagonist, 1 micromol litre(-1) antagonized the inhibitory effects of R(-)-MPPB 90 mg x kg(-1) i.p. In contrast, R(-)-MPPB, S(+)-MPPB 60 and 90 mg x kg(-1) i.p. increased ACh release to 151.8 (6.8)% and 169.6 (11.1)% of the basal release, respectively. CONCLUSIONS: Our results demonstrated that R(-)-MPPB decreased, while S(+)-MPPB increased, rat hippocampal ACh release and that the inhibitory effects of R(-)-MPPB may involve the GABA(A) receptor in vivo. These data imply that changes in hippocampal ACh due to these agents may be related to their central inhibitory and stimulatory actions in vivo.

Acetylcholine↗

PubMed1985

Induction of gamma-glutamyl transpeptidase in primary cultures of normal rat hepatocytes by liver tumor promoters and structurally related compounds.

Rat hepatocytes maintained for up to 6 days in primary culture were used to test a variety of xenobiotics and steroids for effects on the activity of gamma-glutamyltranspeptidase (GGT) in normal cells. In control cultures GGT activity was low and increased slowly with time. When added to cultures for 5 days, a variety of xenobiotics and steroids increased GGT activity to levels 2- to 6-times those of control cultures. Induction of GGT was potentiated for most test compounds by 20-30 nM dexamethasone and diminished by nicotinamide or adenosine-3',5'-monophosphate. Effective non-genotoxic inducers included phenobarbital and some structurally related compounds, p,p'-dichlorodiphenyltrichloroethane,alpha- and gamma-hexachlorocyclohexanes, Aroclor 1254, butyl hydroxytoluene, nafenopin, various estrogens, progesterone, pregnenolone-16 alpha-carbonitrile and cyproterone acetate. A number of compounds including barbituric acid, butyl hydroxyanisole, acetaminophen, saccharin, caffeine, clofibrate and some bile acids failed to induce GGT. Except for 2-acetylaminofluorene and diethylnitrosamine, genotoxic compounds tested did not increase GGT. The results establish that a structurally diverse group of xenobiotics and steroids, many of which are considered to be liver tumour promoters, may directly enhance GGT gene expression in normal hepatocytes. Thus, a variety of compounds used in experimental studies of liver cancer induction as promoters may elevate GGT by mechanism(s) not necessarily related to carcinogenesis.

Animals↗

PubMedDate not supplied

An evaluation and modification of a microdiffusion method for the emergency determination of blood cyanide.

Data are presented to indicate the recovery one can expect with different diffusion times in the microdiffusion procedure for the determination of cyanide using Conway cells. Using a predetermined recovery factor, a diffusion time of 10 min is recommended for emergency situations. In the use of the pyridine-barbituric acid reagent for color development, it was found that the reagents could be added as rapidly as is manually possible and that while the color complex begins to fade as soon as developed, the error after 4 to 10 min ranges from 3 to 9%.

Colorimetry↗

PubMed2002

Interaction of intravenous anesthetics with recombinant human M1-M3 muscarinic receptors expressed in chinese hamster ovary cells.

UNLABELLED: Previous reports suggest that the effects of propofol, ketamine, and thiopental on airway tone may be because of modulation of parasympathetic activity. We examined if these anesthetics interact with recombinant human M1-M3 muscarinic receptors expressed in Chinese hamster ovary cells (CHO-M1, M2, and M3) using the displacement of 0.4 nM of l-[N-methyl-(3)H]scopolamine methyl chloride([(3)H]NMS). In addition, functional studies were performed by fluorometrically monitoring methacholine (1 mM) stimulated intracellular Ca(2+) ([Ca(2+)](i)) responses. Ketamine concentration dependently displaced [(3)H]NMS binding to CHO-M1, M2, and M3 cells with affinity, pK(i) (mean K(i)) values of 4.34 +/- 0.14 (45 micro M), 3.53 +/- 0.10 (294 micro M), and 3.61 +/- 0.02 (246 micro M), respectively. The effects at M1 were in the clinical range. Ketamine did not affect either basal or methacholine stimulated increase in [Ca(2+)](i) in CHO-M1 cells. Thiopental significantly displaced [(3)H]NMS binding to M3 (pKi [mean Ki] = 4.12 +/- 0.06 [75 micro M]) but not M1 or M2 receptors. Thiopental (10(-5)-10(-3) M) concentration dependently inhibited methacholine stimulated increase in [Ca(2+)](i) in CHO-M3 cells. Propofol and barbituric acid did not interact with any muscarinic receptor subtype. We suggest that at the level of [Ca(2+)](I), thiopental may possess M3 antagonist activity, whereas there are no functional consequences of the interaction of ketamine with the M1 receptor. IMPLICATIONS: In this study using recombinant human M1-M3 muscarinic receptors, we show that for agonist-stimulated increases in intracellular Ca(2+) thiopental acts as a M3 antagonist.

Anesthetics, Intravenous↗

PubMed1988

Dry reagent immunoassay for measuring phenobarbital in serum and plasma.

A reagent strip has been developed for measuring phenobarbital concentrations in serum or plasma. This strip utilizes the apoenzyme reactivation immunoassay system (ARIS) and is designed for use with the Ames Seralyzer reflectance photometer. The test takes 85 s and compares strip reactivities with a two-point calibration line that is stored in the instrument. Within-run precision coefficient of variation ranges from 2.4 to 4.1% over five concentrations while the between-run precision ranges from 2.3 to 4.9%. Results obtained with clinical serum samples correlated well (r greater than 0.99) with those obtained by a fluorescence polarization immunoassay (TDx). The strips crossreact with other barbituric acid derivatives that are not coadministered with phenobarbital. Crossreactivity to the metabolite p-hydroxyphenobarbital is sufficiently low as to not interfere in the usual specimens. Samples that are hemolyzed, highly icteric, or from uremic patients should be avoided. This assay is a rapid and convenient method for monitoring serum or plasma phenobarbital concentrations. It is particularly well suited for decentralized test sites, such as emergency rooms, urgent care centers, and physician's offices.

Apoenzymes↗

PubMed1994

Simultaneous determination of felbamate, primidone, phenobarbital, carbamazepine, two carbamazepine metabolites, phenytoin, and one phenytoin metabolite in human plasma by high-performance liquid chromatography.

An isocratic liquid-chromatographic method employing one extraction step has been developed for the quantitation of five drugs and three metabolites in human plasma. The method uses 0.100-ml aliquots of human plasma and two internal standards. Chromatographic conditions include a 4.6 mm x 150 mm Spherisorb ODS2, 3 microns a high-performance liquid chromatography, (HPLC) column, a phosphate buffer-acetonitrile-methanol (700:160:140) mobile phase, and ultraviolet (UV) absorbance detection at 210 nm. Analytes and linear quantitation ranges (microgram/ml) were felbamate (FBM) 0.391-200; primidone (PRIM), 0.098-100; phenobarbital (PHENO), 0.195-100; carbamazepine (CBZ), 0.195-100; phenytoin (PHT), 0.195-200. For CBZ-transdiol (CBZ-TR) CBZ-epoxide (CBZ-EP), and the PHT metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), the range was 0.049-25.0 micrograms/ml. Ethosuximide, methsuximide, 2-methyl-2-phenyl-succinimide (methsuximide metabolite), 2-ethyl-2-phenyl malonamide (PRIM metabolite, 5-ethyl-5-(4-hydroxyphenyl)-barbituric acid (PHENO metabolite), and mephenytoin do not interfere with quantitation of the above compounds.

Anticonvulsants↗

PubMed2005

Structural basis for inhibition of Escherichia coli uridine phosphorylase by 5-substituted acyclouridines.

Uridine phosphorylase (UP) catalyzes the reversible phosphorolysis of uridine to uracil and ribose 1-phosphate and is a key enzyme in the pyrimidine-salvage pathway. Escherichia coli UP is structurally homologous to E. coli purine nucleoside phosphorylase and other members of the type I family of nucleoside phosphorylases. The structures of 5-benzylacyclouridine, 5-phenylthioacyclouridine, 5-phenylselenenylacyclouridine, 5-m-benzyloxybenzyl acyclouridine and 5-m-benzyloxybenzyl barbituric acid acyclonucleoside bound to the active site of E. coli UP have been determined, with resolutions ranging from 1.95 to 2.3 A. For all five complexes the acyclo sugar moiety binds to the active site in a conformation that mimics the ribose ring of the natural substrates. Surprisingly, the terminal hydroxyl group occupies the position of the nonessential 5'-hydroxyl substituent of the substrate rather than the 3'-hydroxyl group, which is normally required for catalytic activity. Until recently, inhibitors of UP were designed with limited structural knowledge of the active-site residues. These structures explain the basis of inhibition for this series of acyclouridine analogs and suggest possible additional avenues for future drug-design efforts. Furthermore, the studies can be extended to design inhibitors of human UP, for which no X-ray structure is available.

Amino Acid Sequence↗

PubMed1990

Evaluation of the properties of a new pour denture base material utilizing a modified technique and initiator system.

A new denture base system, Provac, has been developed for complete and partial dentures, and for relining. The Provac material is methyl methacrylate, which cures with the aid of barbituric acid. In this study the physical and mechanical properties of the new resin were investigated and compared with those of a conventional autopolymerizing material (Croform) and a conventional heat polymerizing material (Trevalon). It was found that the dimensional accuracy of Provac was better than that of the conventional heat-curing material, Trevalon, and the denture was finished more easily and quickly. The physical and mechanical properties of Provac resin were found to be similar to those of the other two materials, and conformed to the International Specifications for denture base materials. The residual monomer levels in Provac material were always higher than the minimal obtainable values associated with conventional heat-cured materials when these were polymerized with a terminal boil during the curing cycle.

Acrylates↗

PubMed1983

Proline dehydrogenase from Escherichia coli K12. Properties of the membrane-associated enzyme.

We have examined the oxidative activities of inverted cytoplasmic membrane preparations from Escherichia coli bearing proline dehydrogenase. Our measurements include both direct substrate:2,6-dichloroindophenol and substrate:O2 oxidoreductase assays and the 9-aminoacridine fluorescence assay for proton translocation, employing succinate and NADH dehydrogenases as comparative standards. Our data show the following. (a) Membranes prepared in a new buffer system bear proline dehydrogenase that is stable in both activity and membrane association. This membrane-associated enzyme shows an apparent Km for proline 20-fold lower than that estimated from the solubilized and purified enzyme. (b) Electrons are transferred from proline to O2 via the respiratory chain since proline utilization requires porphyrin synthesis and it is coupled to trans-membrane proton translocation. (c) Patterns of inhibition by 5-ethyl-5-isopentyl barbituric acid (Amytal) and 2-heptyl-4-hydroxyquinoline-N-oxide (HpHOQnO) suggest that parallel pathways of electron flux from NADH and proline converge at a cyanide-sensitive terminal oxidase. Succinate:O2 and succinate:DCIP oxidoreductase activities are stimulated by HpHOQnO and Amytal, and the former is inhibited by cyanide in this system. (d) Amytal is a non-competitive inhibitor of proline dehydrogenase. (e) Analysis of our fluorescence data suggests that Amytal and HpHOQnO dissipate delta pH at concentrations as low as 5 mM and 8.5 microM, respectively, in this system.

Cell Membrane↗

PubMed1983

Metabolic resistance: the protection of enzymes against drugs which are tight-binding inhibitors by the accumulation of substrate.

Blockade of a metabolic pathway by interaction of a drug with a particular 'target enzyme' results in depletion of essential end-products of the pathway and accumulation of intermediates prior to the blockade. Metabolic resistance to a particular drug can arise if the substrate of the inhibited enzyme accumulates to levels sufficiently high to compete effectively with the inhibitor, leading to restoration of full activity of the metabolic pathway after a transitory delay. Such resistance has recently been demonstrated in vitro for the interaction of the tight-binding inhibitor N-phosphonacetyl-L-aspartate (PAcAsp) with the aspartate transcarbamoylase activity of the trifunctional protein which initiates pyrimidine biosynthesis in mammals [Christopherson, R. I. and Jones, M. E. (1980) J. Biol. Chem. 255, 11381-11395]. Carbamoyl phosphate, the product of the carbamoyl phosphate synthetase activity of this trifunctional protein, accumulates to a sufficiently high concentration that the inhibitory effect of PAcAsp is effectively abolished. We have developed a theoretical model for metabolic resistance which quantitatively accounts for these experimental data. This model has been used to simulate the interaction between the following potential or proven anti-cancer drugs and their target enzyme, under conditions similar to those which would occur in vivo: PAcAsp with aspartate transcarbamoylase; various OMP analogues [the 5'-monophosphates of 6-azauridine, pyrazofurin and 1-(beta-D-ribofuranosyl)-barbituric acid] with OMP decarboxylase; 5-fluorodeoxyUMP with thymidylate synthase; methotrexate with dihydrofolate reductase; and deoxycoformycin with adenosine deaminase.

Aspartate Carbamoyltransferase↗

PubMed1984

Metabolic resistance to tight-binding inhibitors of enzymes involved in the de novo pyrimidine pathway. Simulation of time-dependent effects.

When a tight-binding inhibitor interacts with a target enzyme of a metabolic pathway, the end products of the pathway are depleted and the substrate(s) for the inhibited reaction accumulate. The accumulating substrate(s) can reach a concentration which is sufficiently high that the inhibition is effectively reversed, with restoration of the original flux through the inhibited reaction. We have recently developed a theoretical model for this phenomenon which we have called 'metabolic resistance' [R. I. Christopherson and R. G. Duggleby (1983) Eur. J. Biochem. 134, 331-335]. In the present communication, we have successfully used the technique of numerical integration to simulate the effects of inhibition of several enzymes in the pathway of pyrimidine biosynthesis. Utilizing appropriate dissociation constants and enzyme concentrations for the inhibited systems, these simulations are consistent with published experimental data for the interactions of N-phosphonacetyl-L-aspartate (P AcAsp) with mammalian aspartate transcarbamoylase in vitro [R. I. Christopherson and M. E. Jones (1980) J. Biol. Chem. 255, 11 381 -11 395] and of 5-fluorodeoxyuridine 5'-phosphate (FdUMP) with thymidylate synthetase in vivo [R. G. Moran, C. P. Spears, and C. Heidelberger (1979) Proc. Natl Acad. Sci. USA 76, 1456- 1460]. In addition we present a simulation of the expected effect in vivo of phosphoribofuranosyl barbituric acid (BMP), a tight-binding inhibitor of OMP decarboxylase [H. L. Levine, R. S. Brody, and F. H. Westheimer (1980) Biochemistry 19, 4993- 4999]. This simulation shows that on addition of BMP, there is a sequential depletion of all pyrimidine intermediates between UMP and dCDP and a concomitant accumulation of OMP. Eventually, OMP reaches a new steady-state concentration and the concentrations of the depleted intermediates rise to their original levels. We have simulated the depletion of dCDP at various concentrations of BMP; since dCDP is comitted to DNA synthesis we can integrate the dCDP concentrations over time to calculate the amount of DNA synthesis and thereby predict the delay in cell division which would be elicited by BMP. This form of analysis may help to explain in quantitative terms why inhibitors of nucleic acid biosynthesis have a selective toxicity for rapidly growing tumour cells.

Carboxy-Lyases↗

PubMed1992

Biosynthesis of vitamin B12. Transformation of riboflavin 2H-labeled in the 1'R position of 1'S position into 5,6-dimethylbenzimidazole.

The 5,6-dimethylbenzimidazole moiety of vitamin B12 is formed from riboflavin in aerobic and some aerotolerant bacteria. Thereby C1' of riboflavin is transformed into C2 of the vitamin B12 base. In the present publication a study on this transformation with riboflavin 2H-labeled in the 1'R or 1'S position is described. This study was undertaken in order to find out if one of the two hydrogens at C1' is transferred to C2 of 5,6-dimethylbenzimidazole. The 2H-labeled riboflavin samples were synthesized starting from unlabeled or 1-2H-labeled ribose and 3,4-dimethylaniline yielding N-beta-D-ribopyranosyl-3,4-dimethylaniline. The unlabeled riboside was reduced to N-D-ribityl-3,4-dimethylaniline with sodium cyanoborotrideuteride, the 2H-labeled riboside with sodium cyanoborohydride. The ribityl derivatives were transformed into N-D-ribityl-2-phenylazo-4,5-dimethylaniline, and condensed with barbituric acid to riboflavin. The reduction of the ribosyl compound to the ribityl derivative is only partially stereospecific. Thus the riboflavin synthesized from unlabeled ribose had a 2H ratio of 3/1 (1'R/1'S), the riboflavin obtained from D-[1-2H1]ribose of 1/3 (1'R/1'S). The 2H content in these positions was determined from the 1H-NMR spectra. These spectra showed also that 1 mol 2H/mol riboflavin was present in position 1'. The deuterated riboflavin samples were incubated under aerobic conditions with broken cell preparations of Propionibacterium shermanii. The deuterium content of the 5,6-dimethylbenzimidazole isolated was determined by mass spectrometry and by 1H NMR. These measurements revealed that the hydrogen in the pro-S position at C1' of riboflavin is retained during 5,6-dimethylbenzimidazole formation, and is thus found at C2 of this base.

Benzimidazoles↗

PubMed1989

Mechanisms of action of new antiepileptic drugs.

Our understanding of how new antiepileptic drugs work mirrors what we know about how currently marketed antiepileptic compounds exert their action--that information is scarce and elusive. The mechanism of action of antiepileptic drugs is nevertheless inextricably linked to epileptogenesis itself, and investigations of several promising new compounds are underway to establish the levels at which these drugs act. Compounds act on synapses and membranes as well as affecting receptors, neurotransmitters, and peptides. The most extensive data are available on drugs that inhibit the action of GABA or its receptors, including new benzodiazepine-like agents and barbituric-acid derivatives. The few drugs that act by inhibiting the effects of excitatory amino acids are reviewed. Finally, the maximal electroshock test is an empirical method to determine the antiepileptic properties of a drug; several agents under development have been effective in this screening technique.

Acetamides↗

PubMed1981

A polymeric film responding in diffusion properties to environmental pH stimuli: a model for a self-regulating drug delivery system.

A new polymeric film, ethylene-vinyl-NN-diethylglycinate random copolymer, has been studied to evaluate possible applications of such a material to produce controlled release dosage forms. Protonation of the substituted amino groups took place to different extents according to environmental pH conditions. The polymeric film proved to be permeable only to uncharged species, the rate of diffusion of which increased with the increasing charge of the membrane. This effect might be related to strong polymer-proton interactions affecting structure and transport properties of the film and enhancing the solvation process. The charged form of a number of barbituric acid derivatives did not diffuse through the membrane. The uncharged forms permeated the polymeric sheeting at rates consistent with their partition coefficients and which increased with the increasing charge of the polymer.

Chemical Phenomena↗

PubMed2003

Phenobarbital alters hepatic Mrp2 function by direct and indirect interactions.

Phenobarbital (PB) treatment impairs the biliary excretion of some organic anions. One mechanism may involve direct competition for biliary excretion by PB and/or a PB metabolite. Alternatively, PB may alter the expression and/or function of hepatic organic anion transport proteins. The role of multidrug resistance-associated protein 2 (Mrp2) in the biliary excretion of PB and metabolites was studied using isolated perfused livers (IPLs) from Wistar and Mrp2-deficient TR- rats. In normal livers, 4.19 +/- 0.53% of the PB dose was recovered in bile as PB metabolites [2.21 +/- 0.69% as 5-ethyl-5-(4-OH phenyl) barbituric acid (PBOH)-glucuronide; 1.98 +/- 0.09% as PBOH-sulfate]. In TR- livers, only PBOH-sulfate was recovered in bile (0.35 +/- 0.16% of dose) during the 2-h perfusion. Mrp2 message was increased (2.3-fold) by PB pretreatment (80 mg/kg i.p. x 4 days) but decreased to control values after a 48-h washout. Mrp2 protein was increased slightly in PB-treated livers and remained slightly elevated after a 24-h washout, but it was decreased significantly to 62 +/-7% of control values after a 48-h washout. The 120-min cumulative biliary excretion of the Mrp2 substrate 5-(and-6)-carboxy-2', 7'-dichlorofluorescein in IPLs from PB-treated rats after a 48-h washout was significantly lower than in vehicle-treated livers (66.3 +/- 9.2% versus 83.4 +/- 2.4% of the dose, respectively). These data support two mechanisms for impaired biliary excretion of some organic anions by PB treatment: 1) PBOH-glucuronide is a substrate for Mrp2 and may compete with other organic anions for biliary excretion and 2) Mrp2 protein expression and functional capacity is decreased 48 h after PB treatment.

ATP-Binding Cassette Transporters↗

PubMed1961

Rifomycin. XIV. Production of rifomycin B.

The production of a fraction of the rifomycin complex (rifomycin B) by Streptomyces mediterranei has been described. Both qualitative and quantitative aspects of the fermentation are determined by suitable agitation-aeration parameters. In addition to conventional nutrient ingredients, the presence of some of the barbituric acid derivatives was found to be essential for rifomycin B production. An attempt was made to explain the mode of action of these compounds.

Anti-Bacterial Agents↗

PubMed2006

An efficient synthesis of novel pyrano[2,3-d]- and furopyrano[2,3-d]pyrimidines via indium-catalyzed multi-component domino reaction.

Various novel pyrano [2,3-d]pyrimidines 5 and furopyrano [2,3-d]pyrimidines 7 were synthesized in 80-99% yields via a multicomponent domino Knoevenagel/hetero-Diels-Alder reaction of 1,3-dimethyl barbituric acid with an aromatic aldehyde and ethyl vinyl ether/2,3-dihydrofuran in presence of 1 mol% of indium(III) chloride. The reaction also proceeds in aqueous media without using any catalyst, but the yield is comparatively less (65-70%).

Journal Article↗