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After partial hepatectomy rats were used as a model of patients with liver tumor after extensive hepatectomy. Supplementation of a nucleotide and nucleoside mixture to the total parenteral nutrition solution in rats after 70% hepatectomy resulted in earlier restoration of the nitrogen balance in the first 3 days than the solution without this supplementation. This supplementation had no unfavorable effects on the compositions of the blood and urine, and particularly the metabolites of nucleic acids such as uric acid, beta-alanine, and beta-aminoisobutyric acid. A suitable ratio of nucleotides plus nucleoside to amino acids was tentatively concluded to be 1:2 g N with a calorie supply of 400 kcal.
Reversed-phase liquid chromatography is used for the separation of 5-fluorouracil, its deoxyribo- and ribonucleosides and nucleotides. The bases and nucleosides are easily separated from their naturally occurring analogues on an octadecyl silica column eluted with 2.10(-2) M KH2PO4 (pH 5.0) containing 5% (v/v) of methanol. This system can be applied to the measurement of 5-fluoro-2'-deoxyuridine serum levels down to 0.1 microgram/ml. Addition of small amounts (10(-3) M) of tetrabutylammonium phosphate to the eluent results in a large retention increase for the nucleotides, while the capacity ratios of the bases and nucleosides remain unchanged. The influence of the tetrabutylammonium phosphate and ammonium phosphate concentrations and pH of the eluent on the various k' values was investigated. Evidence is presented indicating that the quaternary ammonium compound is adsorbed onto the octadecyl silica surface: nucleotides are probably retained as adsorbed tetrabutylammonium ion-pairs.
A study has been undertaken of conformational parameters in single crystal structures of nucleosides and nucleotides using the techniques of helical conformational analysis. A "quasi-helix" was generated from the geometry of base-paired structures, using published data extracted from the Cambridge structural database. A total of 54 base-pairs were found in these structures, for each of which were calculated hydrogen bond parameters, propeller twist, buckle and C1'-C1' separations. These were analysed according to various classifications. Propeller twists are found to show a wide range of values and the magnitude of twist appears to be unrelated to hydrogen bond parameters or C1'-C1' separation. The values of the buckle parameter vary over a smaller range of values and are unrelated to propeller twist magnitude. There is found to be a greater tendency to form homo-base-pairs among compounds containing adenine bases.
Leukotriene A(4) (LTA(4)) is a chemically reactive conjugated triene epoxide that is formed by 5-lipoxygenase and is an intermediate in the formation of the biologically active eicosanoids leukotriene B(4) and leukotriene C(4). The present study was undertaken to determine whether or not LTA(4) could serve as an electrophilic species that nucleosides and nucleotides could attack, ultimately resulting in a covalent adduct. Electrospray ionization mass spectrometry and tandem mass spectrometry were used to study the covalent binding of LTA(4) with uridine, cytidine, adenosine, and guanosine. The reaction with guanosine was found to yield five major and at least six minor adduct species. Reversed phase HPLC and mass spectrometric data suggested that the guanosine attacked LTA(4) either at carbon-12 or carbon-6 with opening the epoxide at carbon-5 to yield a series of adducts characterized by the molecular anion [M-H](-) at m/z 600.3. Reactions of LTA(4) with mixtures of nucleosides and nucleotides revealed that guanine-containing nucleosides were the most reactive toward LTA(4). The facility of the reaction of guanine with LTA(4) raises the possibility that this intermediate of leukotriene biosynthesis formed on or near the cellular nuclear envelope may react with nucleosides and nucleotides present in RNA or DNA.
A relationship was found between the N-glycosyl bond length in beta-nucleosides and nucleotides and the spatial relationship of this bond with respect to the lone-pair orbitals on the furanose ring oxygen. This relationship may be relevant to the geometry involved in the hydrolysis of the glycosidic bond.
The detection of alkylated bases at the nanogram level is reported. The reaction is based on two steps, first, chlorination of the bases and, secondly, spraying the chlorinated product with o-tolidine solution to give a dark blue color. The detection of nucleotides and nucleosides is also possible. The optimum conditions and the possible mechanism of the reaction are discussed.
The design and synthesis of potential antitumor antimetabolites 2'-deoxy-2'-hydroxylaminouridine (2'-DHAU) and -cytidine (2'-DHAC) are described. We found that 2'-DHAC in neutral solution generated 2'-aminoxy radicals at room temperature. 2'-DHAC inhibited the growth of L1210 and KB cells, with IC50 values of 1.58 and 1.99 microM, respectively, more potently than 2'-DHAU, with IC50 values of 34.5 and 27.3 microM, respectively. 2'-DHAC was effective against 9 human cell lines, with IC50 values of in the micromolar range. The in vivo antitumor activity of 2'-DHAC was also examined using the mouse leukemia P388 model, which gave a T/C value 167%. Phosphorylation of 2'-DHAC by uridine/cytidine kinase was essential for its cytotoxicity, as suggested by a competition experiment using several common nucleosides. Inhibition of DNA synthesis was the predominant mechanism of action of 2'-DHAC, although it has a ribo-configuration.
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Pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety were designed as potential antitumor and/or antiviral agents. Pd (O)-catalyzed reactions of enantiomerically pure (+)-(1R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-1-(ethoxycarbonylo xy)-2- cyclopentene (9) with N3-benzoylthymine and -uracil gave carbocyclic nucleosides 10 and 11. Subsequent Pd (O)-catalyzed reactions of N3-benzoyl-1-[(1R,4S)-4-(ethoxycarbonyloxy)-2-cyclopenten-1- yl]thymine (14) and -uracil (15) with O-benzylhydroxylamine smoothly gave the hydroxyamino-substituted carbocyclic nucleosides 16 and 17. From these nucleosides, the target compounds were prepared after deprotection or further reactions. The 2',3'-didehydro-2',3'-dideoxythymidine (D4T) analogue 20 was the most effective compound, with IC50 values of 27.3 and 34.5 microM against KB and L1210 cells in vitro. Carbocyclic analogues of uridine and cytidine (29 and 32) were less effective than 20 against both cell lines.
In the present experiment, the effect of a nucleoside-based mixture (OG-VI) on protein synthesis was evaluated. Twenty male Wistar rats weighing about 200g underwent 70% hepatectomy by the Higgins-Anderson's method. All animals were administered standard TPN solution just after operation. The control group received only standard TPN (S-TPN) and the experimental group was given TPN containing 13% v/v of OG-VI (OG-TPN). The rates of whole body protein turnover, synthesis and breakdown measured by the Picou & Taylor-Roberts method with 15N-glycine on the 3rd day after operation. Nitrogen balance on the 1st and 3rd postoperative day and the cumulative nitrogen balance in the OG-TPN group were significantly higher than in controls. Moreover, in the OG-TPN group, protein turnover and protein synthesis were significantly more increased than in the control group. It was thus concluded that the increased protein synthesis, rather than the alteration in protein breakdown, accounted for the good nitrogen balance in the OG-TPN group. The present results strongly suggest that the OG-VI nucleoside and nucleotide mixture improves protein metabolism in hepatectomized rats and helps promoting protein synthesis and turnover after surgical stress.
Although there are studies that report the effects of dietary nucleoside and nucleotide mixtures on the immune response, none are concerned with the role in allergic disease. This study evaluated the effect of dietary nucleic acid mixture (NAM) on mice with a nasal allergy model. One group of mice was supplemented with a 0.5% NAM and the other two groups were fed with a nucleic acid-free diet with 20% casein that served as sensitized and nonsensitized controls. The mice of the NAM group and the sensitized control group were sensitized in two courses by 2 microl of 5% 2,4-toluene diisocyanate (TDI), whereas the nonsensitized control was given 2 microl of ethylacetate instead of TDI. On the 28th day, an allergy was provoked with 4 microl of 2.5% TDI and the allergic responses were observed for 10 minutes. Results showed that the NAM diet group had more severe symptoms of itching, rhinorrhea, snorting, and irritability compared with the controls; also observed were a high incidence of sneezing at 34.7 +/- 4.0 in NAM compared with 19.0 +/- 3.0 (P < 0.001) in sensitized controls and 2.8 +/- 0.7 in nonsensitized controls. From this study, it can be concluded that diets supplemented with nucleic acid mixture contribute to the severity of murine allergic rhinitis.
Reversed-phase high-performance liquid chromatography using a C18 column with volatile buffers as the eluant was applied to the separation of a number of nucleosides and nucleotides. Groups of seven nucleosides and five nucleoside monophosphates were separated isocratically employing 0.1 M trimethylammonium acetate and 2% acetonitrile at pH 7.0. Groups of seven nucleoside diphosphates and seven nucleoside triphosphates were separated with 0.1 M triethylammonium bicarbonate and 2% acetonitrile titrated to a pH of 7.1 with acetic acid. The techniques described give resolution and separations comparable to nonvolatile buffers. Moreover, the eluant trimethylammonium acetate or triethylammonium bicarbonate buffer can easily be removed in vacuo from the column effluent, making the technique useful for preparative separations of these compounds. The observed elution pattern of nucleoside phosphates suggests that "paired-ion" chromatography is involved in the separation.
Free radicals produced by the reactions of OH radicals with ribose phosphates, pyrimidine nucleosides and nucleotides in aqueous solutions have been investigated by e.s.r. and spin-trapping techniques. OH radicals were generated by U.V. -photolysis of hydrogen peroxide and short-lived free radicals of the samples were spin-trapped by t-nitrosobutane and identified by e.s.r. spectroscopy. For ribose-5'-phosphate and 2' -deoxyribose-5' -phosphate, e.s.r. spectra observed consisted mainly of singles due to -C(5')H2 radicals which were initiated by H-abstraction from the sugar at the C-4' position and formed by the radical transfer to the C-5' position. It has also been shown that OH radicals abstract a hydrogen atom from the sugar at C-1' and C-5' positions. For cytidine, deoxycytidine, 5'-CMP, 3' -CMP and 5' -dCMP, four radicals have been observed and for uridine, deoxyuridine, 5' -UMP, 3' -UMP and 5' -dUMP, the existence of at least three radical species have been established. In contrast to the case of ribose phosphates, no signals due to -C(5')H2 radicals were detected for pyrimidine nucleosides and nucleotides. The results are discussed in relation to a recent mechanism which described OH-induced strand breaks of DNA.
We summarize our recent work on sonovoltammetric studies of adenine, guanine, thymine, cytosine and their corresponding nucleosides and nucleotides. Ultrasound is found to be an excellent tool to enhance the reliability of determinations of purine and pyrimidine derivatives and can lead to improved analytical performance characteristics and lower detection limits.
Extracellular purines (adenosine triphosphate (ATP), adenosine 5'-diphosphate (ADP) and adenosine) and pyrimidines (uridine 5'-triphosphate (UTP) and UDP) are important signaling molecules that mediate diverse biological effects via P1 and P2 purinergic receptors. The human glioma cell lines U87 MG, U251 MG and U138 MG were treated with purines and pyrimidines for 24 or 48 h and proliferation was measured by [3H]-thymidine incorporation, flow cytometry and cell counting. The studies showed that extracellular nucleotides and nucleosides induce proliferation of the studied glioma cells. Incorporation of [3H]-thymidine followed the order of ATP approximately equal to guanosine approximately equal to inosine approximately equal to adenosine > UTP > ADP while ATPgammaS and 2MeSATP had no effect. The effect of ATP was partially inhibited by suramin and by reactive blue 2 (RB2). Co-treatment with the following antagonists of P1 purinoreceptors DPCPX, CPT or 8PT did not block the effect of adenosine while a specific antagonist of the A3 receptor, MRS1220, totally blocked the effect of adenosine. ATP and adenosine also increased the overall uptake of [3H]-thymidine into the cell, producing a positive effect on the [3H]-thymidine incorporation measurements. These data indicate that the uptake of thymidine and proliferation of gliomas can be induced by purines and pyrimidines via both P1 and P2 purinoceptors.
A high-performance liquid chromatographic method with on-line postcolumn fluorescence derivatization is described for the simple and sensitive determination of guanine and its nucleosides and nucleotides in human erythrocytes. After deproteinization of the biospecimen, guanine and its nucleosides and nucleotides were separated on a reversed-phase column (TSKgel ODS-120T) by gradient elution with methanol in the aqueous mobile phase consisting of tetra-n-propylammonium phosphate (pH 6.0) and phosphate buffer (pH 6.0). The compounds were then automatically converted into fluorescent derivatives by reaction with phenylglyoxal. This derivatization was selective for guanine-containing compounds. The present method permitted the reliable quantification of GDP and GTP in human erythrocytes. The detection limits (at a signal-to-noise ratio of 3) for guanine and its nucleosides and nucleotides were 3.2-10.0 pmol in a 20-microliters injection volume. The concentrations of GDP and GTP in human erythrocytes were 17.2 +/- 6.2 and 40.2 +/- 5.8 nmol/ml, respectively.
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