Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.31 (beta-glucuronidase)
 7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A primary route of inactivation of leukotrienes and their receptor antagonists (LTRA) is metabolism by omega oxidation. SK&F 102922 [5-(2-(8-phenyloctyl)phenyl)-4,6-dithianonanedioic acid] is a LTRA that was designed to be resistant to omega oxidation. Therefore, these experiments were designed to characterize the metabolic fate of [14C]SK&F 102922. Following iv administration of SK&F 102922 (5 mg/kg), 80% of injected radioactivity was excreted in bile in 1 hr. At least five metabolites and parent (18% of administered dose) were present in bile. One metabolite (M1), which accounted for less than 10% of the excreted radioactivity, was monohydroxylated. Three metabolites (M2, M3A, and M3B), which together accounted for greater than 50% of excreted radioactivity, had mass spectra consistent with acyl glucuronides. All three metabolites were alkali labile, whereas only one metabolite (M2) was susceptible to beta-glucuronidase hydrolysis. These data indicate that M3a and M3b are nonglycosidic isomers of M2 that were formed by a nonenzymic reaction involving migration of the aglycone (SK&F 102922) from C-1 to C-2, C-3, or C-4 of glucuronic acid. The 1-O-acyl-beta-glucuronide of SK&F 102922 (M2) exhibits pH dependent rearrangement, with half-lives ranging from 1 to greater than 1000 hr. Therefore, acyl glucuronidation can account for much of the metabolic fate of SK&F 102922 and, potentially, other structurally related LTRAs or endogenous leukotrienes themselves.
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PMID:Metabolism of the leukotriene receptor antagonist 5-(2-(8-phenyloctyl)phenyl)-4,6-dithianonanedioic acid (SK&F 102922) in the guinea pig. Rearrangement of the acyl glucuronide. 135 21

The role of bilirubin conjugates in the formation of pigment gallstones is not known. In this study, we completely solubilized and then analyzed by high-performance liquid chromatography specimens of black pigment gallstones from eight nb/nb mice with hereditary hemolytic anemia. Each dried gallstone specimen of about 200 micrograms was dissolved in 5 ml of dimethyl sulfoxide/0.15 M HCI/50 mM disodium-EDTA (8:1:1 by volume) at room temperature. Stone dissolution was complete by 30 min as monitored by the A456 and direct observation, and no oxidative products of bilirubin were observed in the visible spectrum, 350 to 750 nm. By high-performance liquid chromatography, the intact tetrapyrroles were separated as diconjugated and monoconjugated bilirubins; unconjugated bilirubin was resolved as XIII, IX and III alpha-isomers. The isocratic solvent system used was 0.1 M di-n-dodecylamine acetate/0.1 M di-n-octylamine acetate (4:1, v/v) in methanol, pH 7.4, at a flow of 1 ml per min. Diconjugated bilirubin accounted for 6.0 +/- 2.4 molar % (mean +/- S.E.), monoconjugated bilirubin for 37.4 +/- 8.4% and unconjugated bilirubin for 56.3 +/- 8.9% of the solubilized pigments. The IX alpha-isomer represented 96 +/- 1.9% of the unconjugated bilirubin. The presence of bilirubin conjugates in gallstones was confirmed by ethylanthranilate diazotization: the conjugated azodipyrrole in stone had the same retention time as that of conjugated azodipyrrole from rat and mouse bile. A majority of the bilirubin conjugates was sensitive to beta-glucuronidase of liver origin, indicating that the C-1 glucuronide ester was present.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monoconjugated bilirubin is a major component of hemolysis-induced gallstones in mice. 339 22

In studies designed to reexamine the in vivo occurrence of retinyl phosphate mannose we injected hamsters intraperitoneally with either [2-3H]mannose or [15-3H]retinol and sacrificed the animals 15 min later. The small intestine was removed, the epithelial cells were scraped, and a methanolic extract of the labeled cells was prepared and chromatographed on a Mono Q anion-exchange column. Intraperitoneal administration of either [2-3H]mannose or [15-3H]retinol lead to the formation of a tritium-labeled anionic compound with a retention time on the Mono Q column similar to that of standard retinyl phosphate mannose. However, the biochemical properties of this labeled anionic compound were those expected of an organic acid and not retinyl phosphate mannose. The compound was resistant to both strong acid hydrolysis and mild base hydrolysis, as well as digestion with alpha- or beta-mannosidase, phosphodiesterase I, nucleotide pyrophosphatase, or beta-glucuronidase. When chromatographed on an Aminex HPX-87H organic acid analysis column or a silicic acid column the labeled anionic compound derived from either [2-3H]mannose or [15-3H]retinol comigrated with standard lactic acid. Treatment of the anionic compound derived from [2-3H]mannose with lactate oxidase or L-lactate 2-monooxygenase resulted in the formation of a tritium-labeled product that cochromatographed, respectively, with pyruvate or acetate on the Aminex HPX-87H column. However, treatment of the anionic compound derived from [15-3H]retinol with these same two enzymes resulted in a labeled product that migrated on the Aminex column at the same position as tritiated water. This result demonstrated that the labeled hydrogen was removed during enzymatic digestion and suggested that it was present on the second carbon of lactic acid. During the course of these studies no evidence for the in vivo labeling of a compound with the properties of retinyl phosphate mannose was found. Since [2-3H]mannose leads to labeled lactic acid in vivo the tritium label must not always be lost, as expected, during the entry step into glycolysis in which mannose 6-phosphate is converted to fructose 6-phosphate. The results suggest that an intramolecular hydrogen transfer from the C-2 position of mannose 6-phosphate to the C-1 position of fructose 6-phosphate can occur during the phosphomannose isomerase reaction. The finding that the position of the tritium label on lactic acid derived from [15-3H]retinol is on the second carbon is consistent with it coming from NADH labeled with tritium in the transferable hydrogen which was formed intracellularly during the NAD+-linked oxidation of retinol to retinaldehyde.
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PMID:In vivo formation of tritium-labeled lactic acid from [2-3H]mannose or [15-3H]retinol by hamster intestinal epithelial cells. 357 14

In order to study mechanisms underlying selective enzyme release from human leukocytes during phagocytosis, the effects were studied of compounds which affect microtubule integrity or the accumulation of cyclic nucleotides. Human leukocytes selectively extrude lysosomal enzymes (beta-glucuronidase) from viable cells during phagocytosis of zymosan or immune complexes, or upon encounter with immune complexes dispersed along a non-phagocytosable surface such as a millipore filter. In each circumstance, lysosomal enzyme release was reduced by previous treatment of cells with pharmacological doses of drugs which disrupt microtubules (e.g. 10(-3)-10(-5) M colchicine) or with agents which affect accumulation of adenosine 3'5'-monophosphate (cAMP) (e.g. 10(-3) M cyclic nucleotides and 2.8 x 10(-4)-2.8 x 10(-6) M prostaglandin E (PGE) and A (PGA) compounds). Preincubation of cells with 5 microg/ml cytochalasin B resulted in complete inhibition of zymosan ingestion, but not of adherence of zymosan particles to plasma membranes or selective enzyme release. In this system, in which enzyme release was independent of particle uptake, preincubation of cells with colchicine, vinblastine, dibutyryl cAMP, or PGE(1) also reduced extrusion of lysosomal enzymes. When cell suspensions were incubated with membrane-lytic crystals of monosodium urate (MSU), cytoplasmic as well as lysosomal enzymes were released with subsequent death of the cells. However, enzyme release followed phagocytosis of crystals (as measured by enhanced C-1 oxidation of glucose) and was due to "perforation from within" of the lysosomal membrane, rather than lysis by crystals of the plasma membrane. Enzyme release after MSU ingestion was also reduced when cells were treated with pharmacological doses of the test agents. When cells were killed by Triton X-100, acting on the plasma membrane, C-1 oxidation of glucose was abolished and enzyme release could not be inhibited pharmacologically. These observations suggest that lysosomal enzyme release from human phagocytes can be an active process which accompanies plasma membrane stimulation, is independent of cell death, and may be controlled by cyclic nucleotides and agents which affect microtubules.
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PMID:Mechanisms of lysosomal enzyme release from human leukocytes. I. Effect of cyclic nucleotides and colchicine. 412 73

A major metabolite of the antiepileptic drug valproic acid (VPA) in animals and man is the glucuronic acid conjugate, which is cleaved by incubation with beta-glucuronidase (specific for 1-O-substituted-beta-D-glucopyranosiduronic acids) or hydrolysis in strong acid or alkali. Previous studies revealed that an often substantial proportion of the alkali-labile conjugated VPA in stored urine or bile samples was not hydrolyzed by beta-glucuronidase, suggesting the presence of nonglucuronide conjugates. In the present study, bile from a NaVPA-treated rat was preincubated at 37 degrees C for 3 hr at pH values from -0.8 to 12.9, and then analyzed for nonconjugated VPA, VPA released by hydrolysis with beta-glucuronidase, and VPA released by hydrolysis with alkali. At pH 3-7, all alkali-labile conjugated VPA remained susceptible to beta-glucuronidase hydrolysis, whereas at pH 0-3 and 7-11, a proportion became resistant to the enzyme. GLC and GC/MS analysis of trimethylsilyl derivatives of the intact conjugates revealed the appearance of seven additional peaks, adjacent to the biosynthetic ester glucuronide, of which six were structural isomers and one was a dehydrated species. The data were consistent with acid- and base-catalyzed intramolecular acyl migration of the valproate moiety away from the C-1 position, with subsequent processes of ring-opening, mutarotation, and lactonization yielding structural isomers and lactones which were not substrates for beta-glucuronidase. It was further shown that these rearrangements are time- and temperature-dependent. Consequently, sample handling and storage conditions of ester glucuronides prior to analysis are of prime importance, since hydrolysis with beta-glucuronidase is frequently used for identification and quantification of glucuronides.
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PMID:pH-dependent rearrangement of the biosynthetic ester glucuronide of valproic acid to beta-glucuronidase-resistant forms. 614 92

It is well known to carbohydrate chemists that substituted sugars may undergo facile rearrangement involving the migration of the aglycone from --OH to adjacent --OH. Despite the importance of glycoside conjugates, notably involving glucuronic acid, in the metabolism of xenobiotics, drug metabolism workers have neglected this phenomenon. The potential rearrangement of glucuronides from the biosynthetic C-1 isomers to other positional and stereo-isomers is important, since only 1-O-substituted beta-D-glucosiduronates are substrates for beta-glucuronidase, which is commonly used to identify such conjugates. The intramolecular rearrangement of clofibryl glucuronide has been studied over the pH range 5.2-8.6, by enzymic hydrolysis with beta-glucuronidase, and by HPLC. The amount of clofibric acid released from the conjugate by beta-glucuronidase falls with increasing pH of preincubation above pH 7.4, and this is accompanied by the appearance of three new peaks, each containing both clofibric and glucuronic acids, in the HPLC traces of the incubation mixtures. Similar experiments with three other glucuronides, those of p-nitrophenol, phenolphthalein and 7-hydroxycoumarin, did not show any conversion to beta-glucuronidase resistant forms. The phenomenon of intramolecular rearrangement of ester glucuronides must be considered whenever beta-glucuronidase is used in the analysis of conjugates of carboxylic acids.
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PMID:The formation of beta-glucuronidase resistant glucuronides by the intramolecular rearrangement of glucuronic acid conjugates at mild alkaline pH. 708 76

Human PMN release lysosomal enzymes (beta-glucuronidase, acid phosphatase) when exposed to immune complexes, but do not release cytoplasmic LDH. The cells remain viable, and failure of LDH to appear in supernatants is not due to selective absorption or inactivation. Release of enzymes is not due to platelet contamination and is only partially enhanced by fresh serum. The selective release of lysosomal enzymes after uptake of complexes resembles that induced by inert particles of zymosan, and can be distinguished from the concurrent release of all enzymes after cell death induced by membrane-lytic crystals of MSU. Uptake of complexes, zymosan, or MSU particles is accompanied by concomitant increases in C-1 oxidation of glucose. Although MSU-induced damage can be retarded by the presence of Tris buffer, immune complexes and zymosan selectively release lysosomal hydrolases in the presence or absence of Tris buffer. Agents which elevate the level, within cells, of cAMP (PGE(1), theophylline, 2-CA) and cAMP itself inhibit the selective extrusion of acid hydrolases from leukocytes without affecting the viability of cells. Leukocytes may respond to immune particles by regurgitating a portion of their lysosomal hydrolases during phagocytosis.
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PMID:Mechanisms of lysosomal enzyme release from leukocytes exposed to immune complexes and other particles. 1986 63