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PubMed1986

Liquid chromatographic assay for the measurement of glucuronidation of arylcarboxylic acids using uridine diphospho-[U-14C] glucuronic acid.

A general method for the assay of UDP-glucuronosyltransferase activity towards arylcarboxylic acids (clofibric acid, 1- and 2-naphthylacetic acid) using UDP-[U-14C] glucuronic acid in liver microsomes is described. The 14C-labelled glucuronide was separated by high-performance liquid chromatography, identified by hydrolysis by beta-glucuronidase, characterized by laser desorption mass spectrometry and quantified by scintillation counting. The coefficient of variation of the enzyme activity for the inter-assay repeatability was below 4.5%. As little as 2.5 nmol of the arylcarboxylic acid glucuronides could be detected and precisely quantified. The method was applied to the determination of the apparent kinetic constants for glucuronidation of the acids. Clofibric acid was the best substrate for UDP-glucuronosyltransferase (Vmax/KM, the ratio of the maximum initial velocity and the Michaelis-Menten constant, is 12.3). The two isomers, 1- and 2-naphthylacetic acids, were transformed at a similar rate. However, they exhibited different enzymatic affinities, as the KM values were 1.0 mM and 5.6 mM for 1- and 2-naphthylacetic acid, respectively. This indicates that the spatial organization of the substrates played a critical role in this acyl glucuronoconjugation.

Animals↗
PubMed1993

Determination of the human liver UDP-glucuronosyltransferase 2B4 domains involved in the binding of UDP-glucuronic acid using photoaffinity labeling of fusion proteins.

The interactions between UDP-glucuronic acid and two human liver UDP-glucuronosyltransferase 2B4 peptides (14-150 and 299-446) purified from E. coli as Staphylococcus aureus protein A fusion proteins have been investigated. Photoaffinity labeling with azidonucleotides ([beta-32P]5N3UDP-Glucuronic acid and [beta-32P]5N3UDP-Glucose) and competition experiments with UDP-glucuronic acid and structurally related compounds emphasized the presence of a specific UDP binding site between amino acids 299 and 446. Moreover, competition experiments strongly suggested an interaction between the amino terminal part of the protein and glucuronic acid. It would involve an electrostatic bond in the binding of the cosubstrate via the carboxyl group of UDP-glucuronic acid and a positively charged amino acid of the N-terminal domain of the enzyme.

Affinity Labels↗
PubMed2006

Reconstruction of de novo pathway for synthesis of UDP-glucuronic acid and UDP-xylose from intrinsic UDP-glucose in Saccharomyces cerevisiae.

UDP-D-glucuronic acid and UDP-D-xylose are required for the biosynthesis of glycosaminoglycan in mammals and of cell wall polysaccharides in plants. Given the importance of these glycans to some organisms, the development of a system for production of UDP-D-glucuronic acid and UDP-D-xylose from a common precursor could prove useful for a number of applications. The budding yeast Saccharomyces cerevisiae lacks an endogenous ability to synthesize or consume UDP-D-glucuronic acid and UDP-D-xylose. However, yeast have a large cytoplasmic pool of UDP-D-glucose that could be used to synthesize cell wall beta-glucan, as a precursor of UDP-D-glucuronic acid and UDP-D-xylose. Thus, if a mechanism for converting the precursors into the end-products can be identified, yeast may be harnessed as a system for production of glycans. Here we report a novel S. cerevisiae strain that coexpresses the Arabidopsis thaliana genes UGD1 and UXS3, which encode a UDP-glucose dehydrogenase (AtUGD1) and a UDP-glucuronic acid decarboxylase (AtUXS3), respectively, which are required for the conversion of UDP-D-glucose to UDP-D-xylose in plants. The recombinant yeast strain was capable of converting UDP-D-glucose to UDP-D-glucuronic acid, and UDP-D-glucuronic acid to UDP-D-xylose, in the cytoplasm, demonstrating the usefulness of this yeast system for the synthesis of glycans. Furthermore, we observed that overexpression of AtUGD1 caused a reduction in the UDP-D-glucose pool, whereas coexpression of AtUXS3 and AtUGD1 did not result in reduction of the UDP-D-glucose pool. Enzymatic analysis of the purified hexamer His-AtUGD1 revealed that AtUGD1 activity is strongly inhibited by UDP-D-xylose, suggesting that AtUGD1 maintains intracellular levels of UDP-D-glucose in cooperation with AtUXS3 via the inhibition of AtUGD1 by UDP-D-xylose.

Arabidopsis Proteins↗
PubMed1992

Studies on the biochemical effects of the aldose reductase inhibitor 2,7-difluorospirofluorene-9,5'-imidazolidine-2',4'-dione (Al 1576, HOE 843). Detection of D-glucaric and D-glucuronic acid excretion by high resolution 1H and 13C NMR spectroscopy.

The effects of two aldose reductase inhibitors on the biochemical composition of rat urine were investigated using high resolution 1H and 13C NMR spectroscopy. We report the elevated excretion of D-glucaric acid (DGA) and D-glucuronic acid (GCA) following treatment with 2,7-difluorospirofluorene-9,5'-imidazolidine-2'4'-dione (Imirestat, IM, Al 1576, HOE 843) at 50 mg/kg/day for 1 month, but not with 3-4-bromo-2-fluorobenzyl-4-oxo-3-phthalazine-1-ylacetic acid (Ponalrestat, Statil), dosed at 50 mg/kg/day for 2 weeks. Sugar aciduria was also detected following treatment with the cytochrome P450 inducer phenobarbitone (PB) at 45 mg/kg/day for 1 month, although the qualitative and quantitative pattern of excretion of sugar acids differed greatly between the IM and PB treatment groups. The levels of GCA excreted are elevated 11-fold by IM treatment from 19.0 to 210.0 mumol/24 hr, but only 2.5-fold by PB, from 9.7 to 23.9 mumol/24 hr. DGA was not detectable in control urine, although levels did increase by 30% during the study from 7.5 to 10.9 mumol/24 hr, between day 8 and day 29, with IM treatment, and by 60% from 1.7 to 4.9 mumol/24 hr following PB administration for the same time period. This predominant elevation of DGA and GCA caused by IM treatment far exceeds previous records. In contrast, PB treatment resulted in an increase in intensity of a number of partially resolved sugar resonances, but at a much lower level than resulted from IM treatment. A raised level of DGA and GCA is usually associated with hepatic P450 induction; however, we report here profound DGA and GCA uria as a result of the inhibition of the aldehyde reductase, hexonate dehydrogenase (EC 1.1.1.19, EC 1.1.1.20). This mechanism is not closely linked to P450 induction, corroborating the current view that elevated excretion of DGA is not a reliable indicator of hepatic enzyme induction. This study further demonstrates the use of high resolution NMR spectroscopy in the detection of a novel biochemical effect which may go unnoticed during routine clinical chemistry tests.

Aldehyde Reductase↗
PubMedDate not supplied

Hepatic UDP-glucose and UDP-glucuronic acid synthesis rates in rats during a reduced energy state.

Hepatic synthesis rates of UDP-glucose and UDP-glucuronic acid were determined in rats. Two high pressure liquid chromatographic methods were developed to quantitate and isolate UTP, UDP-glucose, and UDP-glucuronic acid from perchloric acid extracts of rat liver. The specific activities of UTP, UDP-glucose, and UDP-glucuronic acid were determined in liver samples obtained from rats killed by cervical dislocation at various times after [6-14C]orotic acid administration. Synthesis rates were calculated from the rate of change in specific activities of the compound of interest and its immediate precursor and the concentration of the compound of interest. Synthesis rates of UDP-glucose and UDP-glucuronic acid were 102 +/- 9 and 99 +/- 1 nmol X min-1 X g of liver-1, respectively. UDP-glucuronic acid synthesis apparently accounts for most of the UDP-glucose produced during a period (8 a.m.-10 a.m.) when glycogen synthesis is low. The effect of an ethionine-induced reduction of energy state on these basal synthesis rates was examined. UDP-Glucose and UDP-glucuronic acid synthesis rates were decreased by approximately 80%. In summary, the hepatic synthesis rates of UDP-glucose and UDP-glucuronic acid are approximately 100 nmol X min-1 X g of liver-1, and a reduced energy state can decrease these synthesis rates in vivo.

Animals↗
PubMed1979

[Radioenzymatic micromethod for the determination of UDP-glucuronic acid (author's transl)].

A new senitive and specific micromethod for determination of UDP-glucuronic acid is described Extracts from 2.5 mg of liver are incubated with twice washed guinea pig microsomes (as a source of UDP-glucuronyl transferase) and [14C]p-nitrophenol. The content of UDP-glucuronic acid is calculated from the [14C]p-nitrophenyl glucuronide/[14C]p-nitrophenol radioactivity ratio and the known amount of introduced [14C]p-nitrophenol. These values are corrected for losses of UDP-glucuronic acid by a calibration experiment, containing in addition to the aforementioned constituents, a known amount of UDP-glucuronic acid. The mean concentration of UDP-glucuronic acid in mice liver was found to be 171 mumol/kg wet weight.

Animals↗
PubMed1986

Hepatic UDP-glucuronic acid regulation during acetaminophen biotransformation in rats.

Acetaminophen (AA) glucuronidation is capacity limited in several species after administration of high doses and previous data indicate that this phenomenon is due probably to a decrease in the concentration of the reaction cosubstrate UDP-glucuronic acid in liver. The rate-limiting determinant in UDP-glucuronic acid synthesis during AA glucuronidation is not known. The objective of the present study was to determine whether UDP-glucuronic acid synthesis during AA biotransformation is restricted by the supply of UDP-glucose or is limited by UDP-glucose dehydrogenase activity. Adult male Sprague-Dawley rats were injected with 600 mg/kg i.p of AA and liver was obtained 30, 60, 120 and 240 min later for quantitation of UDP-glucose, glycogen and UDP-glucuronic acid. AA was found to decrease markedly UDP-glucuronic acid concentration in liver 30, 60 and 120 min after injection (28, 52 and 58% of control values, respectively). In contrast, hepatic UDP-glucose levels were not altered after 30 min, but were decreased to 55 and 68% of control values 60 and 120 min after AA administration. Glycogen concentrations were decreased at the 30-min time interval only (78% of control). Therefore, maximal depletion of UDP-glucuronic acid occurred when UDP-glucose levels were not affected. UDP-glucose dehydrogenase is subject to product inhibition by NADH and UDP-glucuronic acid and it is possible that NADH accumulates during rapid utilization of UDP-glucuronic acid. Consequently, the effects of AA on cytosolic NADH/NAD ratios in liver were examined by determining the lactate/pyruvate ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1982

The excretion of metabolites of the D-glucuronic acid pathway in human urine. Effect of phenobarbitone administration.

1. The urinary excretion of four metabolites of the D-glucuronic acid pathway, namely D-glucaric acid, free (unconjugated) D-glucuronic acid, L-gulonic acid and xylitol, has been studied in normal male volunteers and in male and female epileptic patients receiving phenobarbitone anticonvulsant therapy. 2. In normal male subjects the urinary excretion of the D-glucuronic acid metabolites, expressed per unit of creatinine, was similar in first void and total (24 h) urine samples and was fairly constant over a period of 4 weeks. 3. In male and female epileptic patients phenobarbitone treatment enhanced the urinary excretion of D-glucaric acid and xylitol and the combined excretion of D-glucaric acid, l-gulonic acid and xylitol. 4. It is suggested that the measurement of a spectrum of urinary D-glucuronic acid metabolites may provide a more reliable index for assessment of the induction of hepatic xenobiotic-metabolizing enzyme activities in man than the determination of urinary D-glucaric acid alone.

Adult↗
PubMed1984

Enzymatic determination of free glucuronic acid with glucuronolactone reductase. I. Isolation and purification of glucuronolactone reductase from rat kidney.

Glucuronolactone reductase [EC 1.1.1.20] from rat kidney was purified over 300-fold by ammonium sulfate fractionation, chromatography on DEAE-cellulose and hydroxylapatite columns, and preparative isoelectric focusing. The substrate specificity of the enzyme in the reduction reaction was broad, and hexuronic acid was one of the best substrates among monosaccharides. Km values for D-glucuronic acid, D-glucuronolactone, D-galacturonic acid, and L-iduronic acid were 6, 9, 4, and 6 mM, respectively. An investigation of the activity for aldose led to the finding that triose and tetrose served as good substrates for this enzyme. However, the activity for aldopentose or aldohexose was less than 1% of that for D-glucuronic acid at the same concentration. The enzyme was inactive towards most hexosamines (galactosamine, mannosamine, N-acetylglucosamine, N-acetylgalactosamine, and N-acetylmannosamine, but not glucosamine), meso-inositol, D-fructose, and tetrasaccharides from hyaluronic acid and chondroitin 4-sulfate. Trisaccharides from hyaluronic acid and chondroitin 6-sulfate which possess glucuronic acid at the reducing end were poor substrates for the enzyme and the activity towards these 4-substituted glucuronic acids was less than 3% of that towards non-substituted glucuronic acid.

Animals↗
PubMed1990

Glycosphingolipids in insects. Chemical structures of two variants of a glucuronic-acid-containing ceramide hexasaccharide from a pupae of Calliphora vicina (Insecta: Diptera), distinguished by a N-acetylglucosamine-bound phosphoethanolamine sidechain.

The two major components of the acidic glycolipid fraction from the pupae of Calliphora vicina were isolated using high-performance liquid chromatography. The acidic moiety was identified as glucuronic acid by beta-glucuronidase cleavage and gas chromatographic analysis as the pentafluoropropionyl derivative. The structures of the carbohydrate moiety were elucidated by peracetylation, methylation, exoglycosidase cleavage, fast-atom-bombardment mass spectrometric and 1H-nuclear magnetic resonance spectroscopic analysis. The only difference between the two hexasaccharide variants was the presence, in one of them, of a between the two hexasaccharide variants was the presence, in one of them, of a phosphoethanolamine (AeP) sidechain on the third sugar of the sequence, i.e. N-acetylglucosamine. The composition of the ceramide moiety was dominated by a C20:0 fatty acid (arachidic acid) and a C14:1 sphingoid base (tetradecasphing-4-enine). The chemical structures of the two insect acidic glycosphingolipids were determined to be: GlcA(beta 1-3)Gal-(beta 1-3)GalNAc(beta 1-4)GlcNAc(beta 1-3)Man (beta 1-4)Glc(beta 1-1)Cer; GlcA(beta 1-3)Gal(beta 1-3)GalNAc(beta 1-4)[2AeP-6]-GlcNAc(beta 1-3) Man(beta 1-4)Glc(beta 1-1)Cer. Such glucuronic-acid-containing insect glycosphingolipids have been given the generic name arthrosides, with the implied synonymity to the gangliosides.

Acetylglucosamine↗
PubMed1979

Degradation of even-numbered reduced and non-reduced hyaluronate oligosaccharides with D-glucuronic acid or N-acetyl-D-glucosamine as non-reducing terminal by chondroitin ABC and AC lyases.

Chondroitin ABC and AC lyases split hexosaminidic linkages in galactosaminoglycans and hyaluronic acid. Even-numbered oligosaccharides from hyaluronic acid with either D-glucuronic acid or N-acetylglucosamine in non-reducing position were used, prior to and after reduction with sodium borohydride, as substrates for chondroitin ABC and AC lyases. These substrates allowed elucidation of the effects of the nearest neighborhood of the bond to be split on the action of the enzymes. The results indicate that chondroitin ABC lyase acts strictly as an endolyase towards hyaluronate and requires the presence of a disaccharide in both reducing and non-reducing positions of the endohexosaminidic bond to be split. None of the hexosaminidic bonds of the tetrasaccharide GlcNAc-GlcUA-GlcNAc-GlcUA is split by chondroitin ABC lyase. In contrast chondroitin AC lyase acts also as an exoglycosidase towards hyaluronate and recognizes only the amino sugar and the uronic acid residue that are linked via the hexosaminidic bond which is split. Thus, the N-acetylglucosamine and glucuronic acid residues at both ends of a tetrasaccharide with the structure GlcNAc-GlcUA-GlcNAc-GlcUA are liberated.

Acetylglucosamine↗
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↗
PubMedDate not supplied

[Preclinical toxicological study of D-glucuronic acid].

A new D-glucuronic acid (DGA) preparation was studied for toxicological safety on a preclinical level. The results obtained upon a single acute DGA administration in rats, mice, and rabbis showed that the drug exhibits moderate toxicity. A one-month treatment of rats (at a single daily dose of 50, 250, and 500 mg/kg, i.p.) and dogs (50 mg/kg, i.v.) induced neither functional nor morphological changes in hemopoietic and lymphoid organs, kidney, heart, as well as in the digestive, nervous, hemostatic, and fibrinolytic systems. The intraperitoneal administration of DGA produced a pronounced local irritation effects. The liver of both rats and dogs treated with DGA showed dose-dependent adipose degeneration, which decreased upon the drug abolition. The administration of DGA in 50, 100, and 250 mg/kg doses led to dose-dependent changes in some characteristics of the reproductive system in rats. DGA did not modify the extent of allergic reactions and showed no immunotoxicant and mutagen properties.

Animals↗
PubMed1970

Measurement of uridine diphosphate glucuronic acid concentrations and synthesis in animal tissues.

1. A method for the isolation from animal tissues of UDP-glucuronic acid by one-dimensional paper chromatography is described and its concentrations in some tissues of several species of vertebrates are reported; the incorporation of [(32)P]-phosphate into UDP-glucuronic acid in vivo was also investigated. 2. The concentration of UDP-glucuronic acid was higher in the liver of rats, rabbits and guinea pigs than in the same tissue of some species of birds, amphibia and fishes; also, the concentration of UDP-glucuronic acid in rat liver, kidney and small intestine was several times lower than that of the same tissues of guinea pigs. 3. The rate of [(32)P]-phosphate incorporation into UDP-glucuronic acid was very high in rat liver and kidney and almost reached equilibrium with the radioactivity of UDP-glucose 30min after the administration of the [(32)P]phosphate.

Animals↗