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PubMed1985

Identification by nuclear magnetic resonance and mass spectrometry of a glucuronic acid conjugate of o-hydroxybenzoic acid in normal urine and uremic plasma.

An endogenous compound (included in the fraction of uremic toxins often called the "uremic middle molecules") was separated from plasma of uremic patients and urine from normal persons. As elucidated by mass spectrometry, enzymatic hydrolysis, and 1H, 13C nuclear magnetic resonance, it appears to be a conjugate of o-hydroxybenzoic acid with glucuronic acid. Its presence in urine of healthy subjects indicates its physiological character.

Adult↗
PubMedDate not supplied

[Assimilation of glucuronic and gluconic acids and ketogluconates by Torulopsis species].

Yeast strains (75) of the Torulopsis genus belonging to 42 species and varieties were studied. Most of them readily assimilated glucono-delta-lactone, with the exception of species that were imperfect analogues of the species Saccharomyces and Kluyveromyces. Only five of the species were capable of assimilating 5-keto-D-gluconate, and merely two of them, namely, T.ingeniosa and T. fragaria, assimilated D-glucuronic acid. These species have a basidiomycetic affinity in chemotaxonomic features.

Candida↗
PubMed1990

Liquid chromatography/mass spectrometry of plasma glucose and secreted glucuronate for metabolic studies in humans.

Negative ion thermospray liquid chromatographic/mass spectrometric methods have been developed for the determination of isotopic enrichments for glucose and acetaminophen-uridine diphosphate glucuronate from (1-2H1)glucose, (1-2H1)galactose and (2-13C)acetate in humans. The error of estimate ranged from below 1% to 5%. The advantages of the method include fast analysis (up to 35 per hour), eased sample preparation, good precision, sensitivity comparable with gas chromatography/mass spectrometry and better than with isotope ratio mass spectrometry.

Blood Glucose↗
PubMed2005

Regioselective conversion of the secondary hydroxyl groups of D-glucuronic acid without the requirement of O-protecting groups.

Trifluoromethanesulfonic acid anhydride (triflic acid anhydride) transforms the bicyclic thiazolidinlactam 1 a into the crystalline elimination product 2, in which all four secondary hydroxyl groups of 1 a are differently functionalized. Compound 2 can then add nucleophiles with high chemo- and stereoselectivity. Altogether, the four secondary hydroxyl groups of D-glucuronic acid are selectively transformed without the need for any O-protecting groups. Minimizing the number of O-protecting groups is a prerequisite for the use of sugar scaffolds in molecular libraries. The hapalosin analogues 15, 16, 19, and 22 outline the strategy towards O-diversified glucose derivatives.

Bridged Bicyclo Compounds↗
PubMed1983

Isolation and characterization of a Chinese hamster ovary cell mutant which accumulates UDP glucuronic acid and requires uridine for growth.

The isolation and characterization of a new pyrimidine requiring mutant of Chinese hamster ovary cells (CHO-Kl, pro-) is described. This mutant (P192) shows an absolute requirement for uridine for growth but is fully capable of pyrimidine nucleotide synthesis. P192 cells accumulate exceedingly large amounts of a compound identified by a variety of chromatographic, chemical, and labelling criteria as UDP glucuronic acid (UDPglcUA). This compound comprises approximately 60% of the acid-soluble nucleotides of P192 cells. Possible genetic mechanisms leading to the phenotype of P192 are examined, and the role of UDPglcUA in cellular metabolism is discussed.

Animals↗
PubMed2001

(1)H nuclear magnetic resonance spectroscopic analysis for determination of glucuronic and iduronic acids in dermatan sulfate, heparin, and heparan sulfate.

(1)H NMR spectroscopy has been established for the determination of uronate residues in glycosaminoglycans (GAGs) such as dermatan sulfate (DS), heparin (HP), and heparan sulfate (HS). Because of variation in the sulfonation positions in DS, HP, or HS, interpretation of spectra is difficult. Solvolysis was applied to remove O-sulfo groups from these GAG chains in dimethyl sulfoxide containing 10% methanol at 80 degrees C for 5 h. In the cases of HP and HS, N-sulfo groups on glucosamine residues were also removed under the same conditions. The resulting unsubstituted amino groups in HP and HS chains were re-N-acetylated using acetic anhydride to obtain homogeneous core structure with the exception of the variation of uronate residues. The contents of glucuronate and iduronate residues in the chemically modified DS, HP, and HS samples were analyzed by 600-MHz (1)H NMR spectroscopy. These methods were applied to compositional analysis of uronate residues in GAGs isolated from various sources.

Animals↗
PubMed1989

A phase I trial of trimetrexate glucuronate (NSC 352122) given every 3 weeks: clinical pharmacology and pharmacodynamics.

Trimetrexate glucuronate (TMTX), a non-classic folate antagonist, has been evaluated clinically on several schedules. We studied TMTX given as an i.v. bolus over 5-30 min every 3 weeks in 44 patients with advanced solid tumors; it was given at doses ranging from 20 to 275 mg/m2. The maximal tolerated dose (MTD) on this schedule is 220 mg/m2, which we also recommend as a starting dose for phase II studies in patients without extensive prior therapy. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for non-toxic patients. The principal dose-limiting toxicity was myelosuppression, although in some patients a flu-like syndrome precluded dose escalation. Significant rash and mucositis also frequently occurred in toxic patients. TMTX plasma concentrations were measured after the first dose and the data were fit by two- or three-compartment mammillary pharmacokinetic models. The TMTX clearance rate was 36.5 +/- 21 ml/min per m2 and did not change with dose; non-linearities with increasing dose were apparent in the steady-state volume of distribution (Vss) and in the terminal disposition half-life (t1/2). The difference between pre-treatment and nadir leucocyte counts was correlated with TMTX dose (r = 0.58; P = 0.0006) and with the area under the concentration vs time curve (AUC) (r = 0.41; P = 0.02). Pre-treatment plasma albumin concentrations correlated weakly with the nadir white blood count (r = -0.36; P = 0.047). Optimal schedules for the administration of TMTX have not been established and phase II trials using both bolus and daily X 5 schedules are under way.

Adult↗
PubMed1989

Automated analysis of 2,3-diamino-2,3-dideoxy-D-glucuronic acid by cation exchange chromatography with fluorometric postcolumn derivatization.

2,3-Diamino-2,3-dideoxy-D-glucuronic acid (diaminoglucuronic acid) occurs as its di-N-acetyl derivative as a unique constituent of some bacterial cell walls. A sensitive chromatographic method for its determination is described. Diaminoglucuronic acid was well separated from glucosamine and galactosamine in about 80 min on a Dionex DC-6A cation exchange column (0.9 x 18 cm, 50 degrees C) with a sodium citrate buffer (pH 5.28) containing boric acid (0.2 M). The amino sugars in the eluate were monitored fluorometrically by postcolumn derivatization with orthophthalaldehyde detection reagent. This method allowed the automated determination of 50-100 pmol of glucosamine, galactosamine, and diaminoglucuronic acid and was applied successfully to the analysis of diaminoglucuronic acid in Propionibacterium acnes cells.

Amino Acids↗
PubMed1994

Characterization of UDP-glucuronic acid transport in rat liver microsomal vesicles with photoaffinity analogs.

The endoplasmic reticulum (ER) of rat liver contains several well characterized UDP-glucuronosyltransferases (UGTs), membrane-bound proteins of 50-54 kDa, and also less well identified UDP-glucosyltransferases, with nucleotide binding sites located on the lumenal surface. There is evidence that the substrates for these enzymes, UDP-glucuronic acid (UDP-GlcUA) and UDP-glucose (UDP-Glc), biosynthesized in the cytosol, are transported into the lumen of the ER via unknown mechanisms, the characteristics of which are poorly defined. A new approach for the study of the transport process has been devised using two active-site directed photoaffinity analogs, [beta-32P]5-azido-UDP-GlcUA and [beta-32P]5-azido-UDP-Glc. Photoincorporation of these probes into the lumenally oriented UGTs of intact rat liver microsomal vesicles was used as an indicator of transport. In intact vesicles, [32P]5N3UDP-GlcUA was efficiently incorporated into UGTs in a time, temperature and concentration dependent manner. In contrast, [32P]5N3UDP-Glc apparently was not transported effectively; maximal photolabeling of the 50-54 kDa proteins by this probe was dependent on detergent disruption of the vesicles. Vesicular uptake of and subsequent photolabeling of the 50-54 kDa proteins by [32P]5N3UDP-GlcUA were inhibited by UDP-GlcUA and 5N3UDP-GlcUA while UDP-Glc, 5N3UDP-Glc, UDP-xylose and UDP-N-acetylglucosamine were less inhibitory, suggesting a high degree of specificity for the uptake/photolabeling process. The anionic transport inhibitors DIDS and SITS inhibited [32P]5N3UDP-GlcUA photoincorporation into UGTs in intact vesicles, but also inhibited photolabeling of these and other enzymes in detergent disrupted vesicles. These data suggest the presence in rat liver microsomal vesicles of a specific, carrier-mediated transport process for UDP-GlcUA which is distinct from the mechanism of UDP-Glc transport.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1995

Membrane translocation and regulation of uridine diphosphate-glucuronic acid uptake in rat liver microsomal vesicles.

BACKGROUND/AIMS: Hepatic glucuronidation is quantitatively the most important conjugation reaction by which an array of endogenous compounds and xenobiotics undergo biotransformation and detoxification. The active site of the uridine diphosphate (UDP) glucuronosyltransferases, which catalyze glucuronidation reactions, has been postulated to reside in the lumen of the endoplasmic reticulum. The aim of this study was to characterize the process whereby UDP glucuronic acid (UDP-GlcUA), the cosubstrate for all glucuronidation reactions, is transported into microsomal vesicles. METHODS: The uptake process was analyzed using rapid filtration techniques, radiolabeled UDP-GlcUA, and rat liver microsomes. RESULTS: Uptake was saturable with respect to time and concentration, inhibited by 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid and 4-acetamido-4'-isothio-cyanatostilbene-2-2'-disulfonic acid, and was osmotically sensitive. Transport was stimulated by Mg2+ and guanosine triphosphate (50 mumol/L) but not guanosine 5'-O-(3-thiotriphosphate) or adenosine triphosphate. Luminal UDP-N-acetylglucosamine (1 mmol/L) produced enhanced uptake of UDP-GlcUA (trans stimulation). In contrast to nucleotide sugar transport in the Golgi apparatus, trans uridine monophosphate and UDP did not alter UDP-GlcUA transport in microsomes, indicating distinct processes. CONCLUSIONS: These data provide unambiguous evidence for the existence of a unique, substrate-specific, regulated, carrier-mediated process that transports UDP-GlcUA into the lumen of hepatocyte microsomes. This transporter may regulate glucuronidation in vivo.

Animals↗
PubMed1990

Hepatic bilirubin and UDP-glucuronate levels in Bolivian squirrel monkeys exhibiting fasting hyperbilirubinemia.

1. Bolivian squirrel monkeys (BoSMs), which are animal models for Gilbert's syndrome, have 40% less hepatic bilirubin UDP-glucuronyltransferase (BR-UPPG-T) activity than Brazilian squirrel monkeys (BrSMs). 2. Although fasting results in similar decreases in hepatic UDP-glucose and UDP-glucuronate levels in both simian subspecies, increased activities (55%) of BR-UDPG-T are induced only in the fasted control BrSMs, which do not exhibit the marked fasting hyperbilirubinemia (FH). 3. Total hepatic bilirubin (BR) concentrations were 50% greater in both fed and fasted BoSMs when compared to BrSMs. 4. Hepatic unconjugated BR levels increase upon fasting only in Gilbert-like BoSMs, reaching concentrations twice that observed in BrSMs. 5. Elevated hepatic BR levels in fasted BoSMs may reflect BR overproduction or inadequate glucuronidation. 6. The increased BR-UDPG-T activity induced in BrSMs during fasting could compensate in-part for the UDPGA depletion and prevent the marked FH as observed in BoSMs.

Animals↗
PubMed1992

Effects of microsomal enzyme inducers upon UDP-glucuronic acid concentration and UDP-glucuronosyltransferase activity in the rat intestine and liver.

This study was conducted to evaluate UDP-glucuronosyl-transferase (UDP-GT) activity, UDP-glucuronic acid (UDP-GA) concentration, and UDP-glucose (UDPG) concentration in the rat intestine and liver following oral administration of butylated hydroxyanisole (BHA), benzo[a]pyrene (BaP), 3-methylcholanthrene (3MC), phenobarbital (PB), pregnenolone-16 alpha-carbonitrile (PCN), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or trans-stilbene oxide (TSO). Microsomal UDP-GT activity was assayed in vitro with acetaminophen (AA), harmol (HA), and 1-naphthol (NA) as the aglycones. Intestinal HA and AA glucuronidation were enhanced by BHA, BaP, and TSO, whereas 3MC, PB, PCN, and TCDD augmented hepatic HA-glucuronide formation and BHA, PB, PCN, TCDD, and TSO significantly increased hepatic AA glucuronidation. All inducing agents except PB and PCN markedly increased both intestinal and hepatic NA glucuronidation. PB, PCN, and TCDD paradoxically decreased intestinal glucuronidation of AA and HA. A similar effect upon hepatic glucuronidation was not observed with any of the agents studied. Hepatic UDP-GA concentration was increased significantly by all inducers studied except PCN and TCDD, whereas hepatic UDPG concentration was increased only by BHA. In the intestine, significant increases in UDP-GA concentration were produced only by BHA and BaP, which also elevated intestinal UDPG. These results demonstrate that microsomal enzyme inducers evoke different effects upon intestinal and hepatic glucuronidation. These differences are manifested with regard to induced changes in UDP-GT activity as well as treatment-induced alterations in UDP-GA content. Thus, the present study further underscores the marked variance of intestinal and hepatic xenobiotic glucuronidation.

Administration, Oral↗
PubMed1992

Determination of the affinity of monoclonal human IgM for myelin-associated glycoprotein and sulfated glucuronic paragloboside.

We determined the association constant of eight monoclonal IgM with two of their targets, i.e. the myelin-associated glycoprotein (MAG) or the sulfated glucuronic paragloboside (SGPG). All IgM had a 10- to 100-fold higher affinity for MAG than for SGPG. The affinity of the different IgM for MAG ranged from 1.3 x 10(-6) to 7 x 10(-9) mol/liter. The Scatchard plots for MAG were curvilinear, half of the sites being of high or low affinity. In contrast, the plots were linear in the assay using SGPG. No obvious correlations were found between the fine specificity of these IgM for the glucuronyl sulfate epitope and their affinity, although most IgM with a high affinity reacted exclusively with SGPG derivatives retaining a sulfate group. There was no parallelism between the severity of the neuropathy and the affinity of the IgM for MAG or SGPG.

Globosides↗
PubMed1988

Distribution of glucuronic acid-and-sulfate-containing glycoproteins in the central nervous system of the adult mouse.

The distribution of glucuronic acid-and-sulfate-containing carbohydrate (GSC) epitope recognized by two monoclonal antibodies, HNK-1 and 4F4, was studied by immunocytochemistry in adult mouse brain. Both antibodies recognized proteins ranging in molecular weight from 60 to above 250 kDa in Western blot but no glycolipid was recognized in the adult brain. With both light and electron microscopic study, two patterns of staining are observed: diffuse neuropil staining, and individual neuronal somata staining. The diffuse neuropil staining is concentrated in discrete anatomically defined areas. At the EM level, this immunoreactivity is associated with numerous dendrites or astrocytic processes. At cell somata, most of neurons are stained only at Golgi apparatus (type 2); however, a distinct population of cells showed membranous staining (type 1) as well. Type 1 membranous immunoreactivity is observed only in membrane adjacent to astrocytic processes. In the cerebral cortex, type 1 neurons are found in layers III and V-VIa of somatosensory cortex, but only in layers V-VIa in most other cortical fields. Other areas containing type 1 neurons include the globus pallidus, the thalamic reticular nucleus, the hippocampus, the deep cerebellar nuclei, and a majority of the primary sensory and motor nuclei in the brainstem. The subpopulation of type 1 neurons show an overlap in distribution and morphology with some GABA-containing cells.

Animals↗
PubMed1981

Development of sarcomas in heterotopically transplanted rat urinary bladder unit exposed to glucuronic acid conjugate of N-hydroxy-4-aminobiphenyl.

The glucuronic acid conjugate of N-hydroxy-4-aminobiphenyl was tested for carcinogenicity using a heterotopically transplanted rat urinary bladder (HTB) diverted from urine flow. A low-grade transitional cell carcinoma developed in 1 of 16 HTB and sarcoma surrounding the Ommaya reservoir connected to HTB in 8 of 16 rats. This unexpected high incidence of sarcomas, not previously observed in HTB-carcinogenesis model, suggested that the glucuronide conjugate of N-hydroxy-4-aminobiphenyl is a locally active carcinogen to mesenchymal cells.

Aminobiphenyl Compounds↗
PubMed1992

Insect glial cells show differential expression of a glycolipid-derived, glucuronic acid-containing epitope throughout neurogenesis: detection during postembryogenesis and regeneration in the central nervous system of Tenebrio molitor L.

The monoclonal antibody CAF-1 recognises a glucuronic acid-containing epitope present on insect acidic glycolipids. Immunohistochemical analysis of the CAF-1 epitope has revealed its differential, temporal and spatial expression during postembryogenesis of the midbrain of Tenebrio molitor. Electron microscopic resolution demonstrated, that the CAF-1 epitope is expressed on glial cells that ensheath the glomeruli of the central body. Concomitantly, a differential pattern of expression was observed in the ventral nerve cord, exhibiting a serially homologous display on glial cells that ensheath neuronal somata in the cell body layer of the thoracic ganglia and ventral associative neuropil. Prominent, topologically restricted CAF-1 immunoreactivity was monitored in termination areas of sensory neurons in the ventral associative neuropil and corresponding nerves 6-48 h after extirpation of the respective sensory neuron somata. CAF-1 expression is correlated with structural reorganisation in postembryonic nervous tissue of T. molitor.

Animals↗
PubMed1991

Circadian variation of hepatic UDP-glucuronic acid and the glucuronidation of xenobiotics in mice.

A circadian cycle in hepatic UDP-glucuronic acid (UDP-GA) concentration was observed in mice that was essentially the reverse of those seen for hepatic glycogen and UDP-glucose. That is, hepatic UDP-GA levels were highest during the fasting period and lowest during the feeding period. However, there was no significant difference between the half-lives or the apparent rates of glucuronidation for either acetaminophen or salicylamide at 8 a.m. and 5 p.m. Therefore, the previously-reported circadian variation in acetaminophen toxicity is probably due to circadian variation in hepatic glutathione levels rather than in hepatic glucuronidation capacity.

Acetaminophen↗
PubMed1995

Assignment of the 750 MHz 1H NMR resonances from a mixture of transacylated ester glucuronic acid conjugates with the aid of oversampling and digital filtering during acquisition.

Many drugs containing carboxylic acid functional groups are metabolised in vivo to ester glucuronides (1-O-acyl-beta-D-glucopyranuronates) and, of these, a number show a propensity to undergo internal isomerisation via a transacylation process, causing the carboxylic acid moiety to migrate successively to the 2-, 3- and 4-positions of the glucuronic acid. These products may be responsible, through reactions with plasma proteins, for some of the allergenic side effects in a number of non-steroidal anti-inflammatory drugs. It is important to understand those properties of the drug molecules which facilitate this reaction, and to this end we have studied the transacylation product formation and reaction kinetics in a series of aryl carboxylic acid glucuronides using NMR spectroscopy. However, the resulting 1H NMR spectra are very complex with much resonance overlap, and recourse to spectral simplification processes is necessary. Here, improvement in spectral resolution by oversampling and digital filtering to restrict the detection range of the spectrometer, thus yielding improved digital resolution, is demonstrated. The approach has been applied to the assignment of a mixture of transacylated ester glucuronides of 2-trifluoromethylbenzoic acid through the use of a two-dimensional 1H-1H TOCSY experiment.

Buffers↗