Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Verlukast, (S)3-((((3-(2-(7-chloroquinolin-2-yl)-(E)-ethenyl)phenyl)- 3-dimethylamino-3-oxopropylthio)methyl)thio)propionic acid, formerly known as MK-679, is a potent leukotriene D4 antagonist. Verlukast was incubated with rat liver microsomes under oxidative conditions to generate five metabolites, which were identified as the four possible isomeric monosulfoxides (M1-M4), and the N-hydroxymethyl amide (M5). This latter metabolite loses the elements of formaldehyde to yield the N-monomethyl amide (M6). These metabolites were isolated from a large microsomal incubation and were characterized by UV, 1H-NMR, and fast atom bombardment-MS. These data were identical to those obtained from synthetically prepared standards. Microsomal incubations of verlukast supplemented with UDP-glucuronic acid yielded the acyl glucuronide metabolite (M7), which was isolated and characterized by UV, 1H-NMR, and fast atom bombardment-M5. Verlukast was regenerated from M7 upon treatment with either beta-glucuronidase or strong aqueous base (pH greater than 11). The metabolites described above were all detected in bile collected from a rat dosed with verlukast.
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PMID:In vitro and in vivo biotransformations of the potent leukotriene D4 antagonist verlukast in the rat. 135 12

The metabolism of KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) in rat, rabbit and dog was studied. The urine of animals dosed with 14C-KC-764 was extracted with ethyl acetate after treatment with beta-glucuronidase and arylsulfatase. The metabolites were purified by TLC and HPLC from the extract. Unchanged KC-764 and 16 metabolites were isolated and their structures were identified or proposed by NMR and MS spectrometry. The metabolism of KC-764 took place by the oxidation of the tetrahydropyridine ring, 6,7-position and 2-methyl group of the pyrazolopyridine ring, and their combinations. The oxidation of the tetrahydropyridine ring was predominant in dog, whereas the oxidation of the pyrazolopyridine ring was more important in rabbit. Rat produced the various metabolites by their combination. 6-Oxo and 6-ureido derivatives of the tetrahydropyridine ring were common major metabolites in all animal species studied.
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PMID:Identification of urinary metabolites of 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine in rat, rabbit and dog. 158 80

Lamotrigine (LTG) is a novel triazine anticonvulsant currently undergoing clinical trials. LTG N-glucuronide, the major human metabolite of LTG, was isolated from human urine by means of XAD-2 column chromatography and semi-preparative HPLC. The structure of the suspected lamotrigine 2-N-glucuronide was proven by mass spectroscopy and NMR spectroscopy, along with chemical and enzymatic hydrolysis studies. High resolution fast atom bombardment mass spectrometry and Electrospray tandem mass spectrometry of the glucuronide gave an M+ ion at 432.0 amu and a fragment ion at 256.0 (M - 176)+ amu. The proton NMR of the glucuronide indicated the presence of a glucuronic acid moiety. A downfield anomeric proton (5.35-5.60 ppm) implied direct attachment to the aromatic triazine ring. Carbon-13 NMR of the glucuronide revealed an upfield shift (delta = -7.0 ppm) of the C-3 carbon of the triazine ring compared to LTG, indicating attachment of the glucuronide to the N-2 position. Chemical degradation or rearrangement of the glucuronide occurs at neutral pH to produce an unknown product (RP-1), while at basic pH a different unknown product (RP-2) is formed. The glucuronide is unusually stable at acidic pH. Treatment of the glucuronide with beta-glucuronidase resulted in hydrolysis to LTG, and enzymatic hydrolysis was inhibited by saccharo-1,4-lactone.
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PMID:Isolation and characterization of a novel quaternary ammonium-linked glucuronide of lamotrigine. 167 89

Metabolites of nitecapone [3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione], a potent new catechol-O-methytransferase-inhibitor, were isolated from human urine both after hydrolysis with beta-glucuronidase and as intact conjugates. Seven phase-I metabolites and corresponding glucuronides were identified using electron ionization and fast atom bombardment mass spectrometry, IR spectroscopy, and proton NMR spectrometry. The most abundant metabolite in urine was the glucuronide of unchanged nitecapone, representing 60-65% of the metabolites found. The main phase-I metabolic reaction was reduction of the side chain double bond and carbonyl groups. One of the major metabolites was formed by cleavage of the side chain by retro aldol condensation. All phase-I metabolites were present mainly as their glucuronic acid conjugates. The 3-nitrocatechol-structure of nitecapone seems to hinder nitro-reduction, catechol-O-methylation, and sulfation reactions.
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PMID:Identification of major metabolites of the catechol-O-methyltransferase-inhibitor nitecapone in human urine. 167 95

After ip administration of 3-tert-butyl-4-hydroxyanisole (3-BHA) to rats, two previously undocumented metabolites 2-tert-butyl-5-methylthiohydroquinone (TBHQ-5-SMe) and 2-tert-butyl-6-methylthiohydroquinone (TBHQ-6-SMe) were identified in the urine by comparison with the authentic samples by GC/MS. In addition to these metabolites, 3-tert-butyl-4,5-dihydroxyanisole was also detected in the urine hydrolyzed by beta-glucuronidase/sulfatase. Administration of tert-butylhydroquinone (TBHQ), an O-demethylated metabolite of 3-BHA, also resulted in the formation of the S-containing metabolites, TBHQ-5-SMe and TBHQ-6-SMe. After incubation of TBHQ with rat liver microsomes in the presence of glutathione (GSH), two metabolites were isolated and purified by HPLC. The metabolites were identified as 2-tert-butyl-5-(glutathion-S-yl)hydroquinone and 2-tert-butyl-6-(glutathion-S-yl)hydroquinone by 1H- and 13C-NMR spectrometry and by fast atom bombardment-mass spectrometry. The formation of TBHQ-GSH conjugates required NADPH, molecular oxygen, and GSH. Cytochrome P-450 inhibitors such as SKF 525-A and metyrapone markedly inhibited the formation of TBHQ-GSH conjugates in vitro. These results suggest that TBHQ is converted by cytochrome P-450-mediated monooxygenases to a reactive metabolite, 2-tert-butyl-p-benzoquinone (TBQ), which then conjugates with GSH to form TBHQ-GSH conjugates. GSH S-transferase activities do not seem to play a role in GSH conjugation reaction to TBQ because cytosol fraction from rat liver homogenates did not enhance the microsome-mediated production of TBHQ-GSH conjugates.
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PMID:Identification and structure characterization of S-containing metabolites of 3-tert-butyl-4-hydroxyanisole in rat urine and liver microsomes. 168 7

We have previously shown that 2-hydroxamino-1-methyl-6-phenylimidazo[4,5-b]pyridine(2-h ydroxamino-PhIP) is the principal metabolite leading to mutations in Salmonella typhimurium TA98 and DNA damage in mammalian cells. In rat hepatocytes this metabolite can be further conjugated to 2-(N-beta-D-glucuronopyranosyl (hydroxamino)-1-methyl-6-phenylimidazo[4, 5-b]pyridine[N(OH)-gluc-PhIP]. Its rate of formation was increased in hepatocytes from polychlorinated biphenyl (PCB)-pretreated animals. This metabolite is the main metabolite of PhIP in bile and it is hydrolyzed both by human and rat intestinal bacteria. Smaller amounts are excreted into urine. The evidence for the proposed structure is based on 1H- and 13C-NMR, beta-glucuronidase-lability giving 2-hydroxamino-PhIP upon hydrolysis and on the results obtained by using biochemical enzyme inhibitors. N(OH)-gluc-PhIP may be important for genotoxic lesions and tumors of 2-amino-1methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) in extrahepatic tissue. In hepatocytes and bile from PCB-pretreated rats a PhIP-glutathione conjugate, 2-glutathionyl-1-methyl-6-phenylimidazo[4,5-b]pyridine (GSH-PhIP) was also found. The evidence for the proposed structure is based on 1H-NMR and high-resolution mass spectrometry. The metabolite can also be produced by a direct nucleophilic substitution of the nitro group in 2-nitro-PhIP by glutathione (GSH) in vitro. The metabolite did not form from 2-hydroxamino-PhIP and GSH either directly or in the presence of glutathione S-transferase. The formation of GSH-PhIP in rat liver and isolated cells only at a high rate of 2-hydroxamino-PhIP formation (PCB-treated animals) indicates that 2-nitro-PhIP may be formed in the liver during such N-oxidation of PhIP.
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PMID:Formation of a glutathione conjugate and a semistable transportable glucuronide conjugate of N2-oxidized species of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rat liver. 174 23

Metabolism of the antiarrhythmic drug encainide was studied in human subjects after a single 50-mg oral dose. Encainide labeled on the carbonyl carbon with 14C and at the benzylic (2'-1-ethyl) carbon with 13C was administered to four normal healthy male subjects. A large proportion of the radioactive dose (42%) was excreted in the urine in the first 24 hr. The total urinary excretion was 47.0 +/- 4.6% and total fecal excretion was 38.7 +/- 5.7% over 5 days. The conjugated metabolites excreted in the urine were hydrolyzed with beta-glucuronidase/arylsulfatase, and were isolated and purified by HPLC. Structural characterization was carried out by a combination of fast atom bombardment-mass spectrometry, gas chromatography/electron impact mass spectrometry, and 1H-NMR spectroscopy. Structures of the metabolites were confirmed by co-elution on HPLC with authentic standards when available. Six metabolites of encainide were identified from the hydrolyzed urine together with unchanged drug. In addition to already known metabolites O-demethyl-encainide, 3-methoxy-O-demethyl-encainide, and N,O-di-demethyl-encainide, three new metabolites were identified: N-demethyl-3-methoxy-O-demethyl-encainide, 3-hydroxy-encainide, and O-demethyl-encainide-lactam. These metabolites accounted for greater than 90% of the radioactivity excreted in the urine. Four major routes of metabolism were identified: first, O-demethylation of the aromatic methyl ether; second, formation of methylated catechol derivatives; third, N-demethylation of the piperidyl nitrogen; and fourth, oxidation at carbon alpha to the piperidyl nitrogen. A plausible scheme for the metabolism of encainide in human subjects is proposed.
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PMID:Structural characterization of urinary metabolites of the antiarrhythmic drug encainide in human subjects. 197 Jul 74

A major metabolite of zidovudine (3'-azido-3'-deoxythymidine, AZT), which previously had not been observed in a variety of experimental animals, was identified in samples of plasma and urine from cynomolgus monkeys and a patient treated with AZT. The urinary recoveries of metabolite from the monkeys and the patient were, respectively, 1.5- and 6.9-fold higher than the recoveries of unchanged drug. The metabolite was purified in gram quantities from the urines of the monkeys and the patient and was identified enzymatically, using beta-glucuronidase and a specific inhibitor of the enzyme, as a glucuronide conjugate of AZT. The metabolite was formed in vitro by incubating AZT with preparations of human liver in the presence of UDP-glucuronic acid. In addition, the metabolite was prepared synthetically and physical characterizations--including microanalysis and UV, IR, NMR and mass spectra--of compound from all three sources were identical and confirmed the metabolite to be the 5'-O-beta-D-glucuronide of AZT.
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PMID:Isolation and characterization of an ether glucuronide of zidovudine, a major metabolite in monkeys and humans. 197 93

Following analysis by reversed-phase HPLC, a previously uncharacterized metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was found in the urine of A/J mice treated with NNK. Treatment with beta-glucuronidase converted the metabolite to a peak that co-eluted with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Treatment with sulfatase or beta-glucuronidase plus saccharic acid 1,4-lactone did not change the retention time of the metabolite. These data suggested that the unknown metabolite was a glucuronic acid conjugate of NNAL. Upon isolation and purification of larger quantities of the metabolite from the urine of A/J mice, CD-1 mice and F344 rats, 1H and 13C NMR and MS confirmed that the unknown metabolite was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butyl beta-D-glucopyranosiduronic acid (NNAL Glu). To determine the quantitative relationship between NNK dose and NNAL Glu production and to compare the importance of glucuronidation relative to other metabolic pathways, [5-3H]NNK was administered to F344 rats and A/J mice at doses of 500-0.005 mumol/kg. At 500 mumol/kg, NNAL Glu accounted for 22% of the total urinary excretion of NNK in A/J mice, and for 8% in F344 rats 48 h after dosing. The proportions of excreted glucuronide and NNAL decreased with diminishing doses of NNK, yielding undetectable levels of each metabolite in both mice and rats at a dose of 0.005 mumol/kg NNK. Since substantial amounts of metabolites formed via alpha-hydroxylation and N-oxidation pathways were observed at the lower doses of NNK, these data demonstrate that NNAL glucuronidation is a quantitatively unimportant metabolic pathway at low doses of NNK.
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PMID:Characterization of a glucuronide metabolite of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its dose-dependent excretion in the urine of mice and rats. 220 95

The metabolism of 14C-labelled 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) was studied in suspensions of hepatocytes isolated from PCB-pretreated rats. The metabolites found after incubation of IQ/MeIQ (0.1 mM) with PCB-pretreated hepatocytes for 3 h were separated into three principal groups: ethyl acetate-extractable metabolites (2-4%), water soluble metabolites (94-98%) and covalently bound metabolites (0.4-0.5%). The water soluble metabolites were separated by HPLC. The metabolites were evaluated by beta-glucuronidase lability, sulphate incorporation and compared with glucuronides formed by microsomes. Mass spectroscopy and proton NMR were also run. The major metabolites formed were a N2-sulphamate, an O-sulphate in position 5 for IQ and 5 for MeIQ and an O-glucuronide in the same position. The MeIQ N2-sulphamate was much less abundant than the IQ N2-sulphamate. When compared with hepatocytes from uninduced rats, it was found that primarily the formation of ring-hydroxylated conjugates increased after PCB-pretreatment. The major ethyl acetate-extractable metabolites were the N2-acetyl derivatives and an unidentified metabolite. A small peak representing the 5-hydroxy-IQ or 5-hydroxy-MeIQ could also be seen in the HPLC chromatogram of the ethyl acetate extractable metabolites. All major water soluble products described in hepatocytes were also found in urine and bile of uninduced rats exposed to IQ/MeIQ in vivo.
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PMID:Characterisation of metabolites of the food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline formed after incubation with isolated rat liver cells. 251 Sep 46


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