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)

Metaproterenol (1-(3,5-dihydroxyphenyl)-2-isopropylaminoethanol) is primarily converted in humans to metaproterenol-3-O-sulfate following oral administration. Ion exchange column chromatography with a gradient of ammonium acetate buffer permitted the isolation of the ammonium salt of metaproterenol-3-O-sulfate from human urine. Treatment of aliquots of the column eluate with purified sulfatase and subsequent HPLC/fluorescence analysis confirmed the presence of metaproterenol. Comparison of the column eluate with a metaproterenol standard by 250-MHz proton-NMR revealed a pattern consistent with monosubstitution of the resorcinol ring. Negative and positive ion fast atom bombardment/mass spectrometry showed the metabolite to have a (M-H)- m/z of 290 and a (M + H)+ m/z ion of 292. These three methods support the structural assignment of metaproterenol-3-O-sulfate. Enzymatic hydrolysis of urine specimens from 29 different subjects with purified beta-glucuronidase as well as beta-glucuronidase-sulfatase mixtures yielded no significant increase in metaproterenol beyond purified sulfatase-treated urine, thus ruling out the presence of a glucuronide of metaproterenol. Approximately 40% of an oral 20-mg dose, given as either a tablet or a solution, was recovered in the urine as metaproterenol-3-O-sulfate. Approximately 5% of the dose was recovered in the unconjugated form. The majority of the dose was excreted over the first 12 hr with a biological half-life of 5-6 hr followed by a slower excretion phase with a half-life of 20 hr.
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PMID:Isolation and characterization of metaproterenol-3-O-sulfate: a conjugate of metaproterenol in human urine. 614 Jan 41

We have isolated an unusual acidic glycolipid which was detected in the lower phase of the Folch partition of the total lipid extract of human liver during a routine isolation of glycosphingolipids. With the solvent systems commonly used for thin-layer chromatography of glycosphingolipids, this glycolipid has a mobility similar to GbOse3Cer, one of the major glycosphingolipids in human liver. Free cholesterol was released from this glycolipid upon treatment with beta-glucuronidase. The electron impact mass spectrum of the permethylated derivative of this glycolipid showed an intense peak at m/e 369 which is consistent with the cholesterol part of the molecule. It also showed m/e 233 and 201 which are derived from the permethylated glucopyranuronosyl residue. The final proof of the structure was accomplished by high resolution NMR spectroscopy which revealed the presence of beta-linked glucopyranuronosyl residue and cholesterol. Thus, the structure of this acidic glycolipid was conclusively established to be 3-O-beta-D-glucopyranuronosyl-cholesterol.
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PMID:Characterization of human liver 3-O-beta-D-glucopyranuronosyl-cholesterol by mass spectrometry and nuclear magnetic resonance spectroscopy. 651 17

The following metabolites of sulfadiazine (S) were isolated from monkey urine by preparative HPLC: 5-hydroxysulfadiazine (5OH), 4-hydroxysulfadiazine (4OH) and the glucuronide (5OHgluc) and sulfate conjugate of 5OH (5OHsulf). The compounds were identified by NMR, mass and infrared spectrometry and hydrolysis by beta-glucuronidase. The analysis of S, the hydroxymetabolites (4OH, 5OH) and conjugates N4-acetylsulfadiazine (N4), 5OHgluc and 5OHsulf in human and monkey plasma and urine samples was performed using reversed-phase gradient HPLC with UV detection. In plasma, S and N4 could be detected in high concentrations, whereas the other metabolites were present in only minute concentrations. In urine, S, the metabolites and conjugates were present. The limit of quantification of the compounds in plasma varies between 0.2 and 0.6 microgram/ml (S 0.31, N4 0.40, 4OH 0.20, 5OH 0.37, 5OHgluc 0.33 and 5OHsulf 0.57 microgram/ml). In urine it varies between 0.6 and 1.1 micrograms/ml (S 0.75, N4 0.80, 4OH 0.60, 5OH 0.80, 5OHgluc 0.80 and 5OHsulf 1.1 micrograms/ml). The method was applied to studies with healthy human subjects and Rhesus monkeys. The metabolites 5OH, 5OHgluc and 5OHsulf were present in Rhesus monkey and not in man. Preliminary results of studies of metabolism and pharmacokinetics in Rhesus monkey and man are presented.
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PMID:Isolation, identification and determination of sulfadiazine and its hydroxy metabolites and conjugates from man and rhesus monkey by high-performance liquid chromatography. 749 69

Healthy subjects were administered single oral doses of 800 mg or 400 mg 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-o ne (L-696,229), a nonnucleoside inhibitor of the human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase (RT). Plasma or urine samples were collected over a period of 48 hr. Pooled plasma (0.5-6 hr) and urine (0-24 hr) samples were analyzed by HPLC-UV and HIV-1 RT inhibition assay using poly rC.dG as a template primer. The parent compound and several common metabolites were detected in both samples. The metabolic profiles were also similar to those obtained from a rat liver slice incubation with [3H]L-696,229. The in vitro metabolites were identified by NMR and MS as 5 alpha-hydroxyethyl- (major), 5,6-dihydrodiol-, 6'-hydroxy-, 6-hydroxymethyl-, and 5-vinyl analogs, and a benzoxazole ring hydrolysis product. Most of the significant metabolites in human plasma and urine were found to be identical to the in vitro metabolites, as established by HPLC-UV and MS. Hydrolysis of the plasma and urine with beta-glucuronidase/sulfatase indicated the presence of significant amounts of conjugates of the parent compound and 5 alpha-hydroxyethyl metabolite. Most of the other primary metabolites were also present in conjugated forms, albeit in small quantities. In addition, two secondary metabolites were isolated and identified from the hydrolyzed urine as 5-acetyl-6'-hydroxy- and 5 alpha-hydroxyethyl-6-hydroxymethyl- analogs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolism of 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2 (1H)-one (L-696,229), an HIV-1 reverse transcriptase inhibitor, by rat liver slices and in humans. 751 52

From human urine the following metabolites of sulfamethoxazole (S) were isolated by preparative HPLC: 5-methylhydroxysulfamethoxazole (SOH), N4-acetyl-5-methylhydroxysulfamethoxazole (N4SOH) and sulfamethoxazole-N1-glucuronide (Sgluc). The compounds were identified by NMR, mass spectrometry, infrared spectrometry, hydrolysis by beta-glucuronidase and ratio of capacity factors. The analysis of S and the metabolites N4-acetylsulfamethoxazole (N4), SOH, N4-hydroxysulfamethoxazole (N4OH), N4SOH, and Sgluc in human plasma and urine samples was performed with reversed-phase gradient HPLC with UV detection. In plasma, S and N4 could be detected in high concentrations, while the other metabolites were present in only minute concentrations. In urine, S and the metabolites and conjugates were present. The quantitation limit of the compounds in plasma are respectively: S and N4 0.10 micrograms/ml; N4SOH 0.13 micrograms/ml; N4OH 0.18 micrograms/ml; SOH 0.20 micrograms/ml; and Sgluc 0.39 microgram/ml. In urine the quantitation limits are: N4 and N4OH 1.4 micrograms/ml; S 1.5 micrograms/ml; N4SOH 1.9 micrograms/ml; SOH 3.5 micrograms/ml; and Sgluc 4.1 micrograms/ml. The method was applied to studies with healthy subjects and HIV positive patients.
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PMID:Isolation, identification and determination of sulfamethoxazole and its known metabolites in human plasma and urine by high-performance liquid chromatography. 782 Feb 61

1. Xanthenone-4-acetic acid (XAA) is an experimental antitumour agent which resembles flavone-8-acetic acid in its induction of cytokine synthesis, nitric oxide production and tumour haemorrhagic necrosis. We have investigated the excretion and metabolic fate of XAA in the BDF1 mouse. 2. XAA was administered intravenously at the maximal tolerated dose (1090 mumol/kg). Urine, plasma and bile were collected and subjected to analysis by hplc. Urine samples demonstrated labile metabolites which released XAA following incubation with beta-glucuronidase/sulphatase or at pH 9.0. The structures of isolated XAA metabolites were characterized by ms or 1H-NMR spectra at 400 MHz. 3. The major metabolite pathway of XAA involves conjugation with glucuronic acid, since the resulting metabolite, XAA acyl glucuronide, accounts for 25% of the dose excreted in the urine. Other metabolite pathways include alpha-oxidation of the acetic acid side chain and aromatic hydroxylation of the xanthenone ring.
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PMID:Disposition of the novel antitumour agent xanthenone-4-acetic acid in the mouse: identification of metabolites and routes of elimination. 797 28

Zenarestat, (3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4- tetrahydroquinazolin-1-yl) acetic acid, an aldose reductase inhibitor is metabolized mainly to the glucuronide in rat and man. The glucuronide was purified from urine of volunteers after ingestion of zenarestat. The structure of the glucuronide was confirmed by LC-MS and NMR as 1-O-acyl-beta-glucuronide. This compound was unstable at physiological pH, being converted to its structural isomers and the aglycone with half-life of 25 min at pH 7.4 and 37 degrees C in aqueous solution. Enzymatic hydrolysis of the glucuronide was studied in urine, blood and tissues. beta-Glucuronidase in human urine contributed little to the hydrolysis of the glucuronide, while in rat urine at pH 6, it was degraded by beta-glucuronidase and the formation of zenarestat was clearly faster than its formation in buffer at pH 6. In both rat and human blood, these reactions were accelerated by albumin, although rat red blood cells may also contribute. The rate of degradation was not affected by red blood cell membrane, haemoglobin, globulin, esterases or beta-glucuronidase. Arylesterase in rat liver, arylesterase and acetylcholinesterase in the kidney, and beta-glucuronidase in both tissues may contribute. Thus, enzymatic degradation of zenarestat 1-O-acyl-beta-glucuronide is dependent not only on pH and temperature but also on species and the type of tissue or body fluid.
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PMID:Enzymatic hydrolysis of zenarestat 1-O-acylglucuronide. 802 35

The metabolism of the experimental antitumor agent acridine carboxamide (AC) has been examined in the male BDF1 mouse. [3H]AC was administered at the optimal single intraperitoneal dose for antitumor activity (410 mumol/kg body weight) and the metabolites in urine, bile, and feces characterized using reversed-phase HPLC. In urine (0-24 hr) the main product appears to be a glucuronide, also present in bile, with lesser amounts of AC, AC-N-oxide, and at least 10 minor products. Biliary excretion of AC metabolites (examined after removal of the gallbladder at the appropriate times) is greatest at 1-2 hr after treatment when at least 14 products are detected, including AC, AC-N-oxide, and other products with UV/visible spectra characteristic of ring hydroxylated and/or acridone derivatives. In feces (0-24 hr) no AC-N-oxide is detected, the major metabolites being two polar species and AC. These polar species are both present in urine and bile where they are increased on incubation with crude beta-glucuronidase. These aglycones have been identified as the 7-hydroxy-9(10H)acridone derivatives of AC and N-monomethyl-AC by [1H]NMR and mass spectrometry. Thus the main pathways of elimination of AC appear to be 1) N-oxidation and 2) 9(10H)acridone formation plus 7-hydroxylation of both AC and its N-demethylated product followed by glucuronidation. Reduction of AC-N-oxide in the gut may allow reabsorption of AC. Both the back-reduction and reabsorption of AC, and enterohepatic circulation of the 7-hydroxyacridone derivatives may contribute to the slow elimination of AC metabolites.
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PMID:Metabolism of the experimental antitumor agent acridine carboxamide in the mouse. 810 May 11

The glucuronidation of the food-borne heterocyclic amine 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) was investigated using hepatic microsomes from several species. PhIP-glucuronic acid conjugates were formed in an NADPH-free system using microsomes from rabbit, dog, guinea pig, and human. Rat, hamster, and mouse microsomes were incapable of directly producing PhIP-glucuronides. The PhIP-glucuronide generated with human microsomes could be resolved by reverse-phase HPLC from that produced with rabbit microsomes. In addition, the human PhIP-glucuronide was susceptible to enzymatic hydrolysis by beta-glucuronidase, whereas the rabbit PhIP-glucuronide did not undergo beta-glucuronidase catalyzed hydrolysis. Fast atom bombardment mass spectrometry of both glucuronides revealed the presence of ions with m/z 401 (M+H+). Rabbit PhIP-glucuronide had a lambda max of 316 nm, similar to that of the parent PhIP. By contrast, a spectral shift in UV absorbance was observed for the human PhIP-glucuronide, which had a lambda max of 305 nm. 1H-NMR spectroscopy and nuclear Overhauser enhancements established that rabbit PhIP-glucuronide was conjugated at the exocyclic amine nitrogen, whereas human PhIP-glucuronide was conjugated at the N3 imidazole ring nitrogen. Km values for PhIP were 0.2-0.3 mM in both species; however, rabbit microsomes exhibited a 22-fold higher Vmax. Collectively, these studies indicate that human and rabbit liver microsomes form structurally different glucuronides of PhIP and suggest the involvement of multiple isoforms of UDP-glucuronosyltransferase. Further, these data suggest that in certain species, including humans, the direct conjugation of PhIP with glucuronic acid may represent a primary route of PhIP metabolism and detoxication.
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PMID:The direct glucuronidation of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) by human and rabbit liver microsomes. 811 24

The metabolism of levonorgestrel (LNG) in the bile following oral administration of the drug was examined in female rat. 1) Within 48 h after administration of 14C-labelled LNG (LNG-14C), 67-82% of the radioactivity was excreted into the bile. 2) Almost all the metabolites in the bile were conjugated with glucuronic acid or sulfuric acid and only a small amount of the unchanged compound was found. 3) After treatment of these metabolites in the bile with beta-glucuronidase and arylsulfatase, more than ten aglycones were detected on TLC. Three main aglycones, M1, M2 and M3, were isolated. They accounted for 68.0, 0.8 and 11.5% of the radioactivity excreted into the bile, respectively. 4) The structures of M1 and M2 were assumed to be 13-ethyl-18,19-dinor-5 alpha,17 beta-pregn-20-yne-3 alpha,17- diol and 13-ethyl-18,19-dinor-5 beta,17 beta-pregn-20-yne-3 alpha,17-diol, respectively, by NMR and LC/MS analyses, and confirmed by direct comparison with respective authentic samples. M3 was assigned to be 13-ethyl-18,19-dinor-5 alpha,17 beta-pregn-20-yne-3 alpha,16 beta,17-triol by NMR, LC/MS and GC/MS analyses and acetonide derivation. 5) Isolation of the glucuronide metabolite, M4, from the bile, was achieved by column chromatography using Amberlite XAD-2 and Sephadex LH-20. Hydrolysis of this compound with beta-glucuronidase released M1 and glucuronic acid. After M4 was converted to an acetylated-methyl ester derivative, the definite structural assignment of M4 was established to be M1-3-O-yl glucuronic acid by NMR analysis. The NOE effect and the value of the corresponding coupling constant of the anomeric proton showed that the glucoside moiety was in the beta configuration. These findings suggested that LNG was predominantly converted to 5 alpha-reduced metabolites and that the 5 beta-metabolite accounted for less than 1% of the total metabolites in female rats. These metabolites were excreted as glucuronides into the bile.
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PMID:[Biliary metabolites of levonorgestrel in rats]. 827 27


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