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PubMedDate not supplied

Isolation, purification, and structure identification of glucuronic acid conjugates of propranolol and alprenolol and their ring-hydroxylated metabolites.

The purpose of this study was to develop a procedure for the isolation, purification, and structure identification of glucuronic acid conjugates of propranolol and alprenolol and their active metabolites, 4-hydroxypropranolol and 4-hydroxyalprenolol. As both aliphatic and aromatic glucuronides may be formed from 4-hydroxypropranolol and 4-hydroxyalprenolol, the structure identification of these conjugates has to be based on the intact conjugates. Using DEAE-Sephadex anion-exchange chromatography, milligram quantities of these glucuronides were isolated from urine of dogs pretreated with propranolol and alprenolol, respectively. A high degree of purification was achieved by reversed-phase HPLC. Structure identification of the methyl ester-trimethylsilyl derivatives was accomplished by electron impact GC/MS. Only one 4-hydroxypropranolol glucuronide was found, having the glucuronic acid linked to the aromatic hydroxyl group. For 4-hydroxyalprenolol glucuronide, however, two structures were identified, one with the glucuronic acid linked to the aromatic hydroxyl group, and the other with the glucuronic acid linked to the aliphatic hydroxyl group of the side chain. Using this analytical approach, 4-hydroxypropranolol glucuronide was identified in the urine of patients on propranolol therapy. In man, as in the dog, only the aromatic glucuronide was found, i.e. containing an unsubstituted beta-blocking side chain.

Alprenolol↗

PubMed1996

Accumulation of xylitol in the mammalian lens is related to glucuronate metabolism.

Cataract remains the major cause of blindness worldwide and a common complication of diabetes. Polyol accumulation in the lens is associated with cataract formation. Here we present evidence for a novel pathway for xylitol production in the lens involving glucuronate metabolism. Xylitol can be produced in rat and bovine lens from glucose, via the enzymes myo-inositol-oxygen oxidoreductase, D-glucuronate reductase, L-gulonate NAD(+)-3-oxidoreductase and L-iditol-NAD(+)-5-oxidoreductase, which have been found in the mammalian lens for the first time. Glucuronate reductase has been purified and was inhibited by thiol quenching reagents. UDP-glucuronyl transferase is also present in mammalian lenses; this enzyme may be an anti-toxic defense mechanism in the lens.

Animals↗

PubMed1994

Determination of the HNK-1 epitope (3-sulphated glucuronic acid) in intact chondroitin sulphates by ELISA. Application to squid skin proteoglycans and their oversulphated carbohydrate structures.

The reactivity of the HNK-1 monoclonal antibody to chondroitin sulphates and derived disaccharides was studied using an ELISA inhibition test. The antibody readily reacted with its specific epitope (3-sulphated glucuronic acid) in intact chondroitin sulphates as well as with the equivalent oversulphated delta 4-disaccharides obtained by chondroitinase digestion and identified as sulphated at C-3 of the hexuronate. It is showed that by using the oversulphated delta 4-disaccharides as standards in an ELISA inhibition test, the amount of 3-sulphated glucuronic acid can be estimated also in the polymer preparations. When applying this ELISA test to the PG populations isolated from squid skin, most of the oversulphation seen in HPLC analyses of these preparations was found to be associated with 3-sulphation of the glucuronic acid.

Animals↗

PubMed1993

High-performance liquid chromatographic method for the determination of norfloxacin glutamate and glucuronate in solid and liquid dosage forms and its application to stability testing.

A simple, precise, stability-indicating reversed-phase high-performance liquid chromatographic method for norfloxacin glutamate and norfloxacin glucuronate in liquid and solid dosage forms is described. Chloronitrodiazepine was used as the internal standard. The eluent used with a C18 bonded phase column was methanol-water-diethylamine (50:50:0.4, v/v/v) (pH* 5.5). The effects of the eluent pH*, the ratio of methanol to water, and the quantity of diethylamine on the retention times of the sample and internal standard were investigated. The method showed good linearity in the range 1-45 micrograms ml-1 for norfloxacin. Solid samples were ground, dissolved in the eluent, filtered, and then determined by this method. Liquid samples were dissolved in the same solvent. The average recoveries of norfloxacin glutamate and norfloxacin glucuronate in their simulated preparations were 99.5% for solid products and 99.8% for liquid products. The method was applied to the study of the thermal stability of the drugs by following the degradation of norfloxacin glutamate and glucuronate in the four products in accelerated tests at 37-80 degrees C for up to 3 months. Shelf-lives at 25 degrees C of the four products were predicted from the results assuming zero- and first-order kinetics of decomposition, and were at least 1.5 years for liquid products and 2 years for solid products.

Chemistry, Pharmaceutical↗

PubMed1999

Effect of nonenzymatic glycation of albumin and superoxide dismutase by glucuronic acid and suprofen acyl glucuronide on their functions in vitro.

Acyl glucuronides bind irreversibly to plasma proteins, and one mechanism proposed for this covalent binding is similar to that for glycation of protein by reducing sugars. Because glycation of protein by glucose and other reducing sugars can alter protein function, this lead to the hypothesis that the glycation of proteins by acyl glucuronides may cause similar effects. When human serum albumin (HSA) was incubated with 0.5 M glucose for 5 days, the unbound fractions of diazepam and warfarin were increased by 41 and 35%, respectively, less than that caused by glucuronic acid which increased the unbound fractions by 90% for diazepam and 420% for warfarin. When HSA was incubated with suprofen glucuronide (SG) at a much lower concentration of 0.005 M for only 24 h, the effects on the unbound fractions of diazepam and warfarin to HSA were altered dramatically with increases of 340 and 230%, respectively. After incubation of superoxide dismutase (SOD) with 0.5 or 1 M reducing sugars for 14 days, the enzyme activity decreased to 82 and 61% of initial levels at day 14, respectively, whereas glucuronic acid almost completely inactivated the enzyme activity over the same period. Even at a very low concentration (0.005 M) of SG, SOD activity was reduced significantly to 11% of initial levels by day 14, which was comparable to the effect by 0.5 and 1.0 M concentrations of glucuronic acid. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and matrix associated laser desorption/ionization time of flight mass spectrometry indicated that several equivalents of reducing sugars or SG became attached to albumin after incubation. These results suggest that acyl glucuronides may affect the function of proteins by the formation of glycated protein in vivo and may be associated with the toxicity of xenobiotics metabolized to labile acyl glucuronides.

Animals↗

PubMed1998

Analysis of glucuronolactone and glucuronic acid in drug formulations by high-performance liquid chromatography.

Glucuronolactone and glucuronic acid in drug formulations and beverages are determined as 1-phenyl-3-methyl-5-pyrazolone (PMP) derivatives using high-performance liquid chromatography. Intra-ester linkage (i.e., the lactone of glucuronolactone) is spontaneously hydrolyzed to free-acid form and is analyzed as the PMP derivative of glucuronic acid. By omitting three evaporation steps in the original derivatization procedure, the total analysis time is shortened to approximately 40 min. Reproducibility of determination is within 4.0% for all drug formulations. The present method satisfies the requirements for routine analysis in the quality control of drug formulations containing glucuronolactone or glucuronic acid.

Antipyrine↗

PubMed1985

Distribution of glucuronic and iduronic acid units in heparin chains.

The distribution of glucuronic and iduronic acid within the chains of anticoagulantly active and inactive beef lung heparin was investigated. A fraction with an average molecular weight of 19,500 was isolated from the heterodisperse mixture and then separated into active and inactive components by affinity chromatography. Each sample was linked through its reducing terminus to tyramine, reduced with sodium borotritide, and bound covalently to Sepharose via an azo bridge. The bound reduced heparin was treated with a limited amount of HNO2 and the degraded fragments were removed. The sections of the chain contiguous with the original reducing terminus were then detached from the insoluble matrix by reaction with sodium dithionite. The recovered polysaccharide was fractionated according to size on Sephadex G-200 and the amount of each uronic acid in the individual fractions was determined. Inactive heparin showed a constant percentage of glucuronic acid in all fragments, i.e. about 8.9% of the total uronic acid. With active heparin the percentage of glucuronic acid increased with the distance from the reducing terminus of the polysaccharide chain, ranging from 9.5 to 20% of the uronic acids. These results suggest that the biosynthesis of active heparin involves unique reactions or specific processing of the macromolecule.

Animals↗

PubMedDate not supplied

[The effect of D-glucuronic acid on the regenerative processes of granulomonocytopoiesis in cytostatic-induced myelodepression].

Whether cytostatic-induced disorders of the blood system can be corrected with D-glucuronic acid has been studied in murine experiments. D-glucuronic acid has been demonstrated to selectively stimulate the processes of bone marrow granulomonocytopoiesis both in intact animals and in rats with bone marrow hypoplasia induced by cyclophosphanum. During D-glucuronic acid administration, stimulation of hemopoietic regenerative processes is followed by the development of granulocyte lineage hyperplasia in bone marrow, the rapid restoration of blood polymorphonuclear leukocyte and monocyte counts and the development of neutrophilia and monocytosis.

Analysis of Variance↗

PubMed1994

Radioassay of UDP-glucuronosyltransferase activities toward endogenous substrates using labeled UDP-glucuronic acid and an organic solvent extraction procedure.

A rapid and sensitive radioassay for measuring UDP-glucuronosyltransferase activities (EC 2.4.1.17) toward the major endogenous substrates hyodeoxycholic and hyocholic acids, bilirubin, estriol, androsterone, and testosterone has been developed. In this assay, 14C-labeled glucuronides are formed from the enzyme-catalyzed reaction of 14C-labeled UDP-glucuronic acid with the unlabeled aglycones. Following incubation, the 14C-labeled glucuronides are separated under acidic conditions from the unreacted 14C-labeled UDP-glucuronic acid by a single extraction with ethyl acetate. The recovery of glucuronides into ethyl acetate was greater than 90%, whereas the carryover of unreacted UDP-glucuronic acid into the organic phase was approximately 0.2%. The reaction products extracted into ethyl acetate were characterized by their mobilities in thin-layer chromatography and identified as glucuronides by their sensitivity to hydrolysis with beta-glucuronidase and inhibition of hydrolysis by the specific beta-glucuronidase inhibitor D-saccharic acid-1,4-lactone. The optimal conditions of enzyme reactions with the individual aglycones have been defined with human liver microsomes as enzyme source. For all aglycones investigated, 10-30 micrograms of microsomal protein are sufficient for enzyme estimation. The assay is applicable to biochemical studies of UDP-glucuronosyltransferases, as well as to measurement of these enzyme activities from small amounts of clinical liver specimens.

Autoradiography↗

PubMed2002

Enzymatically prepared n-alkyl esters of glucuronic acid: the effect of hydrophobic chain length on surface properties.

The effect of hydrophobic chain length on surface properties of enzymatically prepared n-alkyl esters of glucuronic acid are examined. Dynamic parameters from Hua and Rosen's mathematical model and equilibrium surface tension are presented for esters with octyl, decyl, dodecyl, and tetradecyl alkyl segments. Increasing the alkyl chain length has a significant influence on the surface activity. Decyl and dodecyl glucuronate exhibit an interesting adsorption speed associated with foaming capacity. Octyl glucuronate exhibits a micellar organization as its bulk concentration is over 10.68 mM.

Adsorption↗

PubMed2004

A spectrophotometric assay of D-glucuronate based on Escherichia coli uronate isomerase and mannonate dehydrogenase.

Escherichia coli uronate isomerase and mannonate dehydrogenase were overexpressed in E. coli BL21(DE3)pLysS cells and purified to near-homogeneity. The kinetic properties of the two enzymes were investigated. The isomerase was found to be inhibited by EDTA and to be stimulated by Zn(2+), Co(2+), and Mn(2+), but not by Mg(2+) or Ca(2+). Both enzymes were used to develop a sensitive spectrophotometric assay, in which D-glucuronate is converted to D-mannonate with concomitant oxidation of NADH to NAD(+). The sensitivity of this assay permits the detection of less than 1 nmol D-glucuronate. This assay can also be used to determine the concentration of beta-glucuronides and glucuronate 1-phosphate after enzymatic hydrolysis of these compounds with beta-glucuronidase or alkaline phosphatase.

Aldose-Ketose Isomerases↗

PubMed1976

An extracellular fungal polysaccharide composed of 2-acetamido-2-deoxy-D-glucuronic acid residues.

The black yeast-like fungus NRRL YB-4163, now tentatively identified as Rhinocladiella elatior Mangenot, has been found to produce an extracellular microbial polysaccharide composed mainly of 2-acetamido-2-deoxy-D-glucuronic acid residues. Polysaccharide (PS) YB-4163, when isolated in good yield as the neutral potassium salt, dissolves readily in water to produce extremely viscous solutions, which form stable foams and emulsions. By depolymerizing PS YB-4163 with [14C]methanol-HCl, the polysaccharide can be both identified and quantitated radiochemically by determining the individual [14C]methyl glycosides after their separation by paper chromatography. When the methyl glycosides of PS YB-4163 were reduced with NaB3H4, only the methyl glycosides of 2-acetamido-2-deoxy-D-[6-3H]glucose were found. Analysis of the monosaccharide released from carboxyl-reduced PS YB-4163 by acid hydrolysis or methanolysis also showed 2-acetamido-2-deoxy-D-glucuronic acid to be the main constituent. Previously, the only polysaccharides known to be composed entirely or hexosaminuronic acid have been cellular products from pathogens. Of these, the antigenic polysaccharide (SPSA) from Staphylococcus aureus is composed entirely of 2-amino-2-deoxy-D-glucuronic acid, but its amino groups are substituted equally with acetyl and N-acetylalanyl groups. The specific optical rotation of PS YB-4163, [alpha]20D -75 degrees (c 0.5, water), is similar to that of SPSA (-91 degrees), and suggests beta-D-linkages that must be either (1 leads to 3) or (1 leads to 4).

Glucuronates↗

PubMed2005

Glucuronate-modified, long-circulating liposomes for the delivery of anticancer agents.

Liposomes are useful as drug carriers in drug delivery systems, especially for drugs with severe side effects such as antitumor agents. The conventional formulations of liposomes are opsonized by plasma proteins in the bloodstream and trapped in the reticuloendothelial system (RES). Therefore, liposomes with reduced opsonization are expected to have prolonged circulation and to accumulate in tumor tissue due to the leaky endothelium of the tissue. To avoid RES trapping of liposomes, two approaches have been considered. Liposomes may mimic cells circulating in the blood to escape host recognition as foreign substances, or liposomes may be covered with a hydrophilic barrier to escape recognition. For the latter purpose, poly(ethylene glycol) is widely used. For the former purpose, here we focus on the characteristics, in vivo trafficking, and usage in cancer therapy of glucuronate-modified liposomes. Glucuronate-modified liposomes bind to a lower extent to macrophage-like cells in vitro and passively accumulate in tumor tissue evaluated by a technique using positron emission tomography. Glucuronate-modified liposomes with extended circulation are useful for delivering anticancer agents to tumors and reducing the toxic side effects of the agents.

Antineoplastic Agents↗

PubMed1972

Uridine diphosphate glucuronic acid production and utilization in various tissues actively synthesizing glycosaminoglycans.

1. UDP-glucose dehydrogenase has been partially purified from sheep nasal septum cartilage, neonatal rat skin and bovine corneal epithelium. 2. The pH profile, K(m) values for NAD(+) and UDP-glucose, activation energy and molecular weight have been determined for the enzyme from several of the tissues. 3. The sugar nucleotide concentrations in each of the tissues have been related to the spectrum of glycosaminoglycans produced by each tissue. 4. The presence of an allosteric UDP-xylose-binding site distinct from the active site(s) in sheep nasal septum UDP-glucose dehydrogenase has been demonstrated. 5. An active UDP-glucuronic acid nucleotidase has been demonstrated in sheep nasal cartilage. 6. Tissue-space experiments have shown the cell water content of sheep nasal septum cartilage to be 14% of the wet weight. 7. Glucuronic acid 1-phosphate does not occur in measurable amounts in sheep nasal septum cartilage and no UDP-glucuronic acid pyrophosphorylase activity could be detected in this tissue. 8. The inhibition by UDP-xylose with respect to both substrates, UDP-glucose and NAD(+), has been examined, and shown to be allosteric.

Alcohol Oxidoreductases↗

PubMed1974

The copolymeric structure of pig skin dermatan suplhate. Characterization of D-glucuronic acid-containing oligosaccharides isolated after controlled degradation of oxydermatan sulphate.

Selective periodate oxidation of unsubstituted l-iduronic acid residues in copolymeric dermatan sulphate chains was followed by reduction-hydrolysis or alkaline elimination. By this procedure the glucuronic acid-containing periods were isolated in oligosaccharide form; general formula: [Formula: see text] Further degradation of these oligosaccharides with chondroitinase-AC yielded three types of products: (a) sulphated trisaccharide containing an unsaturated uronosyl moiety in the non-reducing terminal and a C(4) fragment in the reducing terminal, DeltaUA-GalNAc-(-SO(4))-R; (b) monosulphated, unsaturated disaccharide, DeltaUA-GalNAc-SO(4) when n is greater than or equal to 2; and (c) N-acetylgalactosamine with or without sulphate. Oligosaccharides containing a single glucuronic acid residue (n=1) comprised more than half of the glucuronic acid-containing oligosaccharides. The terminal N-acetylgalactosamine moiety of the shortest oligosaccharide was largely 4-sulphated, whereas higher oligosaccharides primarily contained 6-sulphated or unsulphated hexosamine moieties in the same position. Moreover, IdUA-SO(4)-containing oligosaccharides were encountered. These oligosaccharides were resistant to the action of chondroitinase-ABC.

Animals↗

PubMed1975

The copolymeric structure of dermatan sulphate produced by cultured human fibroblasts. Different distribution of iduronic acid and glucuronic acid-containing units in soluble and cell-associated glycans.

The structure of dermatan [35S]sulphate-chondroitin [35S]sulphate copolymers synthesized and secreted by fibroblasts in culture was studied. 35S-labelled glycosaminoglycans were isolated from the medium, a trypsin digest of the cells and the cell residue after 72h of 35SO42-incorporation. The galactosaminoglycan component (dermatan sulphatechondroitin sulphate copolymers) was isolated and subjected to various degradation procedures including digestion with testicular hyaluronidase, chondroitinase-AC and-ABC and periodate oxidation followed by alkaline elimination. The galactosaminoglycans from the various sources displayed significant structural differences with regard to the distribution of various repeating units, i.e. IdUA-GalNAc-SO4 (L-iduronic acid-N-acetyl-galactosamine sulphate), GlcUA-GalNAc-SO4 (D-glucuronic acid-N-acetylgalactosamine-sulphate) and IdUA(-SO4)-GalNAc (L-iduronosulphate-N-acetylgalactosamine). The galactosaminoglycans of the cell residue contained larger amounts of IdUA-GalNAc-SO4 than did those isolated from the medium or those released by trypsin. In contrast, the glycans from the latter 2 sources contained large proportions of periodate-resistant repeat periods [GlcUA-GalNAc-SO4 and IdUA(-SO4)-GalNAc]. Periods containing L-iduronic acid sulphate were particularly prominent in copolymers found in the medium. Kinetic studies indicated that the 35S-labelled glycosaminoglycan of the cell residue accumulated radioactivity more slowly than did the glycans of other fractions, indicating that the material remaining with the cells was not exclusively a precursor of the secreted polymers. The presence of copolymers rich in glucuronic acid or iduronic acid sulphate residues in the soluble fractions may be the result of selective secretion from the cells. Alternatively, extracellular, polymer-level modifications such as C-5 inversion of L-iduronic acid to D-glucuronic acid, or sulphate rearrangements, would yield similar results.

Cells, Cultured↗

PubMed1980

Structural studies on heparan sulphate from human lung fibroblasts. Characterization of oligosaccharides obtained by selective periodate oxidation of D-glucuronic acid residues followed by scission in alkali.

1. (3)H- and (35)S-labelled heparan sulphate was isolated from monolayers of human lung fibroblasts and subjected to degradations by (a) deaminative cleavage and (b) periodate oxidation/alkaline elimination. Fragments were resolved by gel- and ion-exchange-chromatography. 2. Deaminative cleavage of the radioactive glycan afforded mainly disaccharides with a low content of ester-sulphate and free sulphate, indicating that a large part (approx. 80%) of the repeating units consisted of uronosyl-glucosamine-N-sulphate. Blocks of non-sulphated [glucuronosyl-N-acetyl glucosamine] repeats (3-4 consecutive units) accounted for the remainder of the chains. 3. By selective oxidation of glucuronic acid residues associated with N-acetylglucosamine, followed by scission in alkali, the radioactive glycan was degraded into a series of fragments. The glucuronosyl-N-acetylglucosamine-containing block regions yielded a compound N-acetylglucosamine-R, where R is the remnant of an oxidized and degraded glucuronic acid. Periodate-insensitive uronic acid residues were recovered in saccharides of the general structure glucosamine-(uronic acid-glucosamine)(n)-R. 4. Further degradations of these saccharides via deaminative cleavage and re-oxidations with periodate revealed that iduronic acid may be located in sequences such as glucosamine-N-sulphate-->iduronic acid-->N-acetylglucosamine. Occasionally the iduronic acid was sulphated. Blocks of iduronic acid-containing repeats may contain up to five consecutive units. Alternating arrangements of iduronic acid- and glucuronic acid-containing repeats were also observed. 5. (3)H- and (35)S-labelled heparan sulphates from sequential extracts of fibroblasts (medium, EDTA, trypsin digest, dithiothreitol extract, cell-soluble and cell-insoluble material) afforded similar profiles after both periodate oxidation/alkaline elimination and deaminative cleavage.

Alkalies↗

PubMed2001

Oxidative decarboxylation of UDP-glucuronic acid in extracts of polymyxin-resistant Escherichia coli. Origin of lipid a species modified with 4-amino-4-deoxy-L-arabinose.

Addition of the 4-amino-4-deoxy-l-arabinose (l-Ara4N) moiety to the phosphate groups of lipid A is implicated in bacterial resistance to polymyxin and cationic antimicrobial peptides of the innate immune system. The sequences of the products of the Salmonella typhimurium pmrE and pmrF loci, both of which are required for polymyxin resistance, recently led us to propose a pathway for l-Ara4N biosynthesis from UDP-glucuronic acid (Zhou, Z., Lin, S., Cotter, R. J., and Raetz, C. R. H. (1999) J. Biol. Chem. 274, 18503-18514). We now report that extracts of a polymyxin-resistant mutant of Escherichia coli catalyze the C-4" oxidation and C-6" decarboxylation of [alpha-(32)P]UDP-glucuronic acid, followed by transamination to generate [alpha-(32)P]UDP-l-Ara4N, when NAD and glutamate are added as co-substrates. In addition, the [alpha-(32)P]UDP-l-Ara4N is formylated when N-10-formyltetrahydrofolate is included. These activities are consistent with the proposed functions of two of the gene products (PmrI and PmrH) of the pmrF operon. PmrI (renamed ArnA) was overexpressed using a T7 construct, and shown by itself to catalyze the unprecedented oxidative decarboxylation of UDP-glucuronic acid to form uridine 5'-(beta-l-threo-pentapyranosyl-4"-ulose diphosphate). A 6-mg sample of the latter was purified, and its structure was validated by NMR studies as the hydrate of the 4" ketone. ArnA resembles UDP-galactose epimerase, dTDP-glucose-4,6-dehydratase, and UDP-xylose synthase in oxidizing the C-4" position of its substrate, but differs in that it releases the NADH product.

Amino Sugars↗