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 mixture of [19-3H]hydroxyandrostenedione and [14C]androstenedione was administered intravenously to 3 women and urine was collected. Only negligible radioactivity could be extracted from the untreated urine. Most of the 14C but only 11% of the 3H was rendered solube in organic solvents by beta-glucuronidase. [3H-19]hydroxyandrostenedione was recovered from this fraction. The conjugates remaining in the urine were extracted into CHCl3 as their pyridinium salts. After solvolysis of the extract with HCLO4 in tetrahydrofuran, neutral metabolites were obtained. Substances extractable from water with organic solvents were obtained by solvolysis of the conjugates with perchloric acid in tetrahydrofuran. [3H-19]hydroxyandrostenedione was identified by isotopic dilution as the major product of solvolysis. Thus, 19-hydroxyandrostenedione undergoes conjugation with glucuronic acid and probably sulfuric acid, most likely at C-19. The major urinary metabolite is the sulfate-like conjugate. Reduction in ring A is less important than for other steroids.
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PMID:Metabolism of 19-hydroxyandrostenedione in human subjects. Urinary excretion of conjugates. 75 31

The metabolism of iv-administered 14C-cortisol (F) by pregnant baboons (107, 124 and 150 days gestation) was compared with that previously reported for nonpregnant animals and with that of animals examined 6-18 h after spontaneous vaginal delivery (178 plus or minus 4 days). Unconjugated, glucuronoside (beta-glucuronidase) and sulfate (H2SO4-ethyl acetate) fractions were extracted with ethyl acetate from urine containing more than 80% of injected 14C. Metabolites of interest were isolated by paper partition chromatography and purified by crystallization and derivative formation. Compared with nonpregnant animals, the following changes (P less than 0.05) were observed in pregnancy: (1) an increase in the percent urinary 14C in the unconjugated fraction and a decrease in the proportion of 14C appearing in the glucuronoside fraction; (2) an increase in excretion of metabolites more polar than the cortols; (3) a decrease in excretion of metabolites less polar than cortisone in the glucuronoside fraction; (4) an increase in unconjugated F excretion. Production rate of F (11.9 plus or minus 0.7 mg/day) estimated by isotope dilution and percent urinary 14C in tetrahydrocortisol and tetrahydrocortisone from the glucuronoside fraction were as in nonpregnant animals. With the exception of an increase in F production (22.7 plus or minus 0.8 mg/day), presumably the result of the stress of labor, F metabolism in the immediate postpartum period was strikingly similar to timals indicates that changes in the mother alone can account for the altered metabolic disposition of F in pregnancy and suggests that the fetus takes little part in metabolism of maternal circulating F.
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PMID:Cortisol metabolism in the baboon during pregnancy and the postpartum period. 109 Apr 36

Acidic sulfate is the most toxicologically important sulfur oxide which exists in the ambient air. To determine if particle size influences toxic effects of sulfuric acid, we investigated the effects of sulfuric acid aerosols of two different sizes on biochemical and cellular parameters of bronchoalveolar lavage fluid from exposed guinea pigs. Guinea pigs were exposed to fine (mass median diameter, 0.3 micron), and ultrafine (mass median diameter, 0.04 micron) sulfuric acid aerosols at 300 micrograms/m3 for 3 hr/day. The animals were euthanized immediately and 24 hr after 1 and 4 days of exposure and lungs were lavaged. Elevated beta-glucuronidase, lactate dehydrogenase activities, and total protein concentration as well as decreased cell viability were observed in the lavage after a single exposure to sulfuric acid aerosols of both sizes. These alterations were small, though statistically significant, and transient. No alteration in these parameters was observed after 4 days of exposure to acid aerosols. In contrast, sulfuric acid-induced alterations in alveolar macrophage function were more pronounced and longer lasting. Immediately after a single exposure to fine acid, there was a 2.7-fold increase in the spontaneous tumor necrosis factor (TNF) release over that in the control group while endotoxin-stimulated TNF release was increased by 2.2-fold. In addition, acid aerosols of both sizes increased the TNF release from macrophages after 4 days of exposure, although there was no clear temporal pattern of induction or recovery. Furthermore, immediately after 4 days of exposure to either fine or ultrafine acid, the amount of H2O2 that could be induced from baseline production by alveolar macrophages was 2.2-fold higher than that of the controls. The phagocytic function of macrophages was also altered by exposure to sulfuric acid aerosols. Twenty-four hours after single or multiple exposure, fine acid enhanced (as high as 78% above control) the in vitro phagocytic activity of alveolar macrophages while ultrafine acid depressed the phagocytic capacity (as much as 50% below that in the control). In addition to these biochemical parameters and cellular functions, we also measured the intracellular pH (pHi) of macrophages harvested after exposures to these acid aerosols using a pH-sensitive fluorescent dye. The resting pHi was depressed after a single exposure to both acid aerosols. The depression in pHi persisted 24 hr after ultrafine acid exposure.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of fine and ultrafine sulfuric acid aerosols in guinea pigs: alterations in alveolar macrophage function and intracellular pH. 155 43

The mutagenicity of 2-hydroxylamino-4-nitrotoluene (2HA4NT), 4-hydroxylamino-2-nitrotoluene (4HA2NT), 2-hydroxylamino-6-nitrotoluene (2HA6NT) or 4-acetylamino-2-hydroxylaminotoluene (4AA2HAT) towards Salmonella typhimurium strains TA98 and TA100 was investigated in the absence and presence of uridine-5'-diphosphoglucuronic acid (UDPGA), acetyl CoA or 3'-phosphoadenosine-5'-phosphosulfate (PAPS) systems, or S9 mix. None of the hydroxylaminonitrotoluenes (2HA4NT, 4HA2NT or 2HA6NT) were mutagenic in both strains while 4AA2HAT was a base-pair substitution mutagen in the UDPGA and PAPS systems. The indirect mutagenic activity was markedly decreased by omission of microsomal fraction (MCF) or UDPGA from the UDPGA system and by addition of beta-glucuronidase to the system. Similarly, the mutagenic activity was markedly decreased either when 105000 X g supernatant fluid (S105), adenosine triphosphate (ATP) or Na2SO4 was omitted from the PAPS system or when pentachlorophenol (PCP) or aryl sulphatase was added to the system. Moreover, the mutagenic activity in either system was markedly decreased by the addition of glutathione (GSH). These results suggested that two esterifications with glucuronic acid and sulfuric acid may play an important role in the appearance of mutagenic activity of 4AA2HAT.
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PMID:Mutagenicity of some hydroxylaminotoluene derivatives towards Salmonella typhimurium in esterification systems. 355 29

Chromatography of benzo[a]pyrene (BaP) sulfate, glucuronide and glutathione (GSH) conjugate standards were examined by h.p.l.c. on a C8 column as modified by various organic acids and solvents. Sulfate and glucuronide standards were positional isomers derived from BaP-1,3,6,7,9 phenols and BaP-GSH conjugates consisted of a racemic mixture of BaP-4,5-GSH. In the absence of acid, BaP conjugates appeared as rapidly eluting, unresolved peaks in aqueous-methanol or acetonitrile gradients or coeluted as broad peaks in a water-propanol gradient, with the exception of BaP-7-OH sulfate which eluted as a distinct symmetrical peak. Addition of acetic or trifluoroacetic (TFA) acids enhanced column retention of BaP conjugates in each solvent system. Upon acidification of mobile phases, BaP-GSH isomers were partially resolved, isomers of BaP sulfates or of BaP glucuronides coeluted, and BaP-7-OH sulfate was resolved from all conjugates. BaP-GSH conjugates were most resolved and preceded elution of other conjugates when TFA was added to mobile phases. BaP sulfates and glucuronides generally coeluted but were partially resolved at 0.1% TFA in a water-methanol gradient. Water-soluble metabolites from cultured hamster embryo fibroblasts (HEF) incubated with [3H]BaP for 24 h were chromatographed by h.p.l.c. in a water-methanol gradient with TFA. BaP glucuronides, consisting of tetraols, triols, quinones, dihydrodiols and phenols eluted as a single peak which could be removed by beta-glucuronidase treatment and organic extraction. BaP sulfates were not detected. The remaining BaP metabolites which were resistant to enzymatic hydrolysis, generally eluted prior to BaP glucuronides suggesting they constitute a family of BaP-GSH derivatives.
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PMID:H.p.l.c. of benzo[a]pyrene glucuronide, sulfate and glutathione conjugates and water-soluble metabolites from hamster embryo fibroblasts. 402 29

A fluorescence high-performance liquid chromatographic method is described for the determination of 17-oxosteroids in biological fluids. 17-Oxosteroids in urine samples are extracted with dichloromethane after enzymatic hydrolysis (beta-glucuronidase-sulfatase), and dehydroepiandrosterone sulfate in serum samples is solvolysed with sulfuric acid in ethyl acetate. 17-Oxosteroids are labeled with dansyl hydrazine in trichloroacetic acid-benzene solution, and then chromatographed on the microparticulate silica gel column using dichloromethane-ethanol-water (400 : 1 : 2) as the mobile phase. The eluate is monitored by a fluorophotometer at 365 nm (excitation) and 505 nm (emission). Linearities of the fluorescence intensities (peak heights) with the amounts of various 17-oxosteroids were obtained between 60 and 1000 pg. The assay proved satisfactory with respect to sensitivity, precision and accuracy. The results obtained by a radioimmunoassay and this method were in good agreement (r = 0.964, n = 81) for serum dehydroepiandrosterone sulfate. This method is also use for the simultaneous determination of individual 17-oxosteroids in serum and urine.
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PMID:Determination of 17-oxosteroids in serum and urine by fluorescence high-performance liquid chromatography using dansyl hydrazine as a pre-labeling reagent. 732 Jan 36

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

The expression and androgen regulation of beta-glucuronidase molecular forms were examined in mouse epididymis, liver, and kidney. Two-dimensional polyacrylamide gel electrophoresis performed under nondenaturing conditions showed that, compared to liver and kidney, which contain four microsomal (M1-M4) and a major lysosomal (L) form of beta-glucuronidase, the epididymis revealed regional differences and tissue specificity in the expression of the various molecular forms of the enzyme. Only the lysosomal form (pI 5.4-6.1) is present in the caput epididymidis while the corpus/cauda contains the lysosomal form, the free X form (pI 5.9-6.3) and the four microsomal forms (X form complexed with egasyn). Mutant mice that lack egasyn have no microsomal forms in the distal epididymis. In epididymal fluid, the lysosomal form is found throughout the epididymis, whereas the X form appears only in the corpus/cauda epididymidis. Sodium dodecyl Sulfate (SDS)-gel electrophoresis and western blot analysis of immunoprecipitated beta-glucuronidase revealed only one band corresponding to the L form (apparent molecular weight 74 kDa) in the caput epididymidis and two bands in the corpus/cauda (apparent molecular weights 73 and 75 kDa), corresponding to L and X forms, respectively. Castration of mice led to the suppression of the regional differences in the appearance of X and M forms in the epididymis. Testosterone supplementation to castrated mice restored the characteristic electrophoretic pattern of beta-glucuronidase in the caput epididymidis. In the liver and kidney, castration has no effect on the expression of the molecular forms, whereas androgen treatment induced the X form in the kidney. Histochemical localization of beta-glucuronidase confirmed the region specificity seen in the epididymis and in addition revealed cell specificity in the expression of beta-glucuronidase. These results indicate that beta-glucuronidase shows tissue specificity and, in the case of the epididymis, region and cell specificity. In addition, the enzyme in the different tissues responds differentially to androgens.
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PMID:Androgen regulation of molecular forms of beta-D-glucuronidase in the mouse epididymis: comparison with liver and kidney. 879 10

The metabolism and excretion of a new anxiolytic/antidepressant drug candidate, CP-93,393, ((7S, 9aS)-1-(2-pyrimidin-2-yl-octahydro-pyrido[1, 2-a]-pyrazin-7-yl-methyl)-pyrrolidine-2,5-dione) were investigated in cynomolgus monkeys after oral administration of a single 5 mg/kg dose of 14C-CP-93,393. Urine, bile, feces, and blood samples were collected and assayed for total radioactivity, parent drug, and metabolites. Total recovery of the administered dose after 6 days was 80% with the majority recovered during the first 48 hr. An average of 69% of the total radioactivity was recovered in urine, 4% in bile, and 7% in feces. Mean Cmax and AUC(0-infinity) values for the unchanged CP-93,393 were 143.2 ng/ml and 497.7 ng.hr/ml, respectively, in the male monkeys and 17.2 ng/ml and 13.7 ng.hr/ml, respectively, in the female monkeys. HPLC analysis of urine, bile, feces, and plasma from both male and female monkeys indicated extensive metabolism of CP-93,393 to several metabolites. The identification of metabolites was achieved by chemical derivatization, beta-glucuronidase/sulfatase treatment, and by LC/MS/MS, and the quantity of each metabolite was determined by radioactivity detector. CP-93,393 undergoes metabolism by three primary pathways, aromatic hydroxylation, oxidative degradation of the pyrimidine ring, and hydrolysis of the succinimide ring followed by a variety of secondary pathways, such as oxidation, methylation, and conjugation with glucuronic acid and sulfuric acid. The major metabolites, oxidation on the pyrimidine ring to form 5-OH-CP-93,393 (M15) followed by glucuronide and sulfate conjugation (M7 and M13), accounted for 35-45% of the dose in excreta. Two metabolites (M25 and M26) were formed by further oxidation of M15 followed by methylation of the resulting catechol intermediate presumably by catechol-O-methyl transferase. A novel metabolic pathway, resulting in the cleavage of the pyrimidine ring, was also identified. The metabolites (M18, M20, and M21) observed from this pathway accounted for 8-15% of the dose. Aliphatic hydroxylation of the succinimide ring was a very minor pathway in monkey. 5-Hydroxy-CP-93,393 (M15, 37-49%), its sulfate and glucuronide conjugates (M7 and M13, approximately 34%), and the pyrimidine ring cleaved product (M18, approximately 8%) were the major metabolites in monkey plasma. The identified metabolites accounted for approximately 90, 93, 97, and 92% of the total radioactivity present in urine, bile, plasma, and feces, respectively. The major in vivo oxidative metabolites were also observed after in vitro incubations with monkey liver microsomes.
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PMID:Metabolism and excretion of a new antianxiety drug candidate, CP-93,393, in cynomolgus monkeys: identification of the novel pyrimidine ring cleaved metabolites. 939 30

Sevoflurane has been used in the last few years in brief surgical operations, either alone or in combination with nitrous oxide. Occupationally exposed groups include anesthesiologists, surgeons and operating room nurses. In 1977 the National Institute for Occupational Safety and Health (NIOSH) recommended that occupational exposure to halogenated anesthetic agents (halothane, enflurane, and isoflurane), when used as the sole anesthetic, should be controlled so that no worker would be exposed to time-weighted average concentrations greater than 2 ppm during anesthetic administration. When halogenated anesthetics are associated with nitrous oxide, NIOSH recommends that the limit value should not exceed 0.5 ppm. We think these recommendations can be extended to sevoflurane. Metabolism of sevoflurane is catalyzed by cytochrome P-450; this involves oxidation of the fluoromethyl side chain of the molecule, followed by glucuronidation. Two urinary metabolites of sevoflurane have been identified: inorganic fluoride (which, however, is not specific) and a non-volatile compound that yields hexafluoroisopropanol (HFIP) when digested with the enzyme beta-glucuronidase. In order to investigate the role of urinary HFIP as an indicator of occupational exposure to sevoflurane (CI, ppm), CI was measured in 145 members of 18 operating room staffs. The measurements of the time-weighted average of CI in the breathing zone were made by means of diffusive personal samplers. Each sampler was exposed during the whole working period. Sevoflurane was desorbed with CS2 from charcoal and the concentrations were measured on a gas chromatograph (GC) equipped with a mass selective detector (MSD). The GC was equipped with a 25 meter cross-linked phenylmethylsilicon column (internal diameter 0.2 mm). GC conditions were as follows: injector column temperature = 200 degrees C; column temperature = 30 degrees C; carrier gas = helium; injection technique of samples = splitless. The analytical conditions for the MSD were the following: ion mass monitored = 131 m/e; dwell time = 50 msec; selected ion monitoring window time = 0.1 amu; electromultiplier = 400 V. Urine samples were collected near the end of the shift and were analyzed for HFIP by head-space gas chromatography after glucuronide hydrolysis. 0.5 ml of urine and 1.5 ml of 10 M sulfuric acid were added to 21.8 ml headspace vials. The vials were immediately capped, vortexed, and loaded into the headspace autosampler. Samples were maintained at 100 degrees C for 30 min, after which glucuronide hydrolysis was 99% complete. Analyses were performed on a GC equipped with a MSD. The analytical conditions for urine analysis were as follows: cross-linked 5% phenylmethylsilicon column (internal diameter 0.2 mm, length 25 m); column temperature = 35 degrees C; carrier gas = helium. The analytical conditions for the MSD were: monitored ions = 51.05 and 99; dwell time = 100 ms; selected ion monitoring window time = 0.1 amu; electromultiplier voltage = 2000 Volt. With our analytical procedure, the detection limit of HFIP in urine was 20 micrograms/L. The variation coefficient (CV) for HFIP measurement in urine was 8.7% (on 10 determinations; mean value = 1000 micrograms/L). The median value of CI was 0.77 ppm (Geometric Standard Deviation = 4.08; range = 0.05-27.9 ppm). The correlation between CI and HFIP (Cu, microgram/L) was: Log Cu (microgram/L) = 0.813 x Log CI (ppm) + 2.517 (r = 0.79, n = 145, p < 0.0001). On the basis of the equation it was possible to establish tentatively the biological limit values corresponding to the respective occupational exposure limit values proposed for sevoflurane. According to our experimental results, HFIP values of 488 micrograms/L and 160 micrograms/L correspond to airborne sevoflurane concentrations of 2 and 0.5 ppm respectively.
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PMID:[Biological monitoring of occupational exposure to sevoflurane]. 1151 50


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