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)

Carbocyclic 2',3'-didehydo-2',3'-dideoxy-guanosine [(-)-CBV] is a potent and selective inhibitor of the human immunodeficiency virus. The formation of the (-)-CBV-5'-O-glucuronide has been reported to be species-specific and stereoselective with rats forming little of the metabolite after administration of (-)-CBV. A series of studies of (-)-CBV disposition in bile duct-cannulated rats and in the in situ perfused rat liver were conducted. Based on differential hydrolysis with beta-glucuronidase, UV, and tandem MS, the 5'-O-glucuronide was unequivocally identified as the major metabolite of (-)-CBV in rat bile. In the bile duct-cannulated rats receiving 14C-(-)-CBV, 15.8 +/- 4.8% of the radioactivity was recovered in bile after > or = 4 hr. The 5'-O-glucuronide accounted for 75% of the biliary radioactivity. In the in situ perfused rat liver, approximately 20.5% of the radioactivity appeared in the bile. Of this (-)-CBV-derived radioactivity, approximately 70% was due to the glucuronide, 13% to unchanged (-)-CBV, and 17% to an unidentified metabolite. These results suggested that biliary excretion was an important source of radioactivity in the feces. A plausible explanation for the lack of excretion of the conjugate in the feces of rats is intestinal degradation of the conjugate catalyzed by the gut microflora. This hypothesis was supported by the demonstration that rat cecal contents efficiently hydrolyzed (-)-CBV-5'-O-glucuronide in bile to (-)-CBV under anaerobic conditions.
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PMID:Glucuronidation as a transient intermediate metabolic step in the elimination of (-)-carbovir. Identification of (-)-carbovir-5'-O-glucuronide in rat bile. 790 54

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

Dietary fat, protein and fibre have been shown to modulate cancer risk in humans and the present study examined the biological effects in human-flora-associated (HFA) rats of altering intake levels within the normal human range. Two control groups, one HFA and the other germfree (GF), consumed a human diet low in fat, fibre and beef for 4 weeks; three other groups consumed human diets similar except for independent 3-fold increases in fat, beef protein or fibre. After 2 weeks on the diets, magnetically recoverable microcapsules were given orally to the rats and subsequently recovered from the faeces to assess endogenous cross-linking agents. After 4 weeks, measurements were made of gut microfloral enzyme activities, hepatic activation of dietary mutagens and hepatic DNA adducts by 32P-postlabelling. Activation in vitro of the dietary mutagens 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by hepatic S9, formation of endogenous hepatic DNA adducts in vivo and the beta-glucuronidase activity of caecal contents were all increased in the sequence high fat > high fibre > high beef = control. Of the two DNA adducts found in all HFA rats, only one was present in GF controls, indicating that the human gut microflora (subject to human dietary modulation) either releases a DNA-adducting product able to act outside the gastrointestinal tract, or stimulates the generation of such a product by mammalian processes. Caecal nitrate reductase activity was highest in rats fed the high beef diet, whilst entrapment of cross-linking agents was highest in those fed the high fibre diet. These results show that risk-related components of human diets interact with human gut microflora to modulate the production of endogenous DNA-adducting and cross-linking substances.
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PMID:Effects of risk-associated human dietary macrocomponents on processes related to carcinogenesis in human-flora-associated (HFA) rats. 838 Oct 55

The terminal bowel is congenitally aganglionic in ls/ls mice. The condition has been associated with an overabundance of laminin and other matrix molecules. Aggregation ls/ls<==>C3H chimeric mice and interspecies mouse<==>quail chimeras were constructed to test the hypothesis that the aganglionosis arises because the ls/ls gut and not the neural crest is abnormal. Demonstration of beta-glucuronidase activity permitted genotypically ls/ls and C3H cells to be distinguished in the ls/ls<==>C3H chimeras. Aganglionosis did not occur in the ls/ls<==>C3H mice and ls/ls neurons were observed in the terminal bowel. Following bactransplantation of control segments of mouse gut into quail host embryos, mouse cells migrated to host targets normally colonized by cells from the neural crest; moreover, quail crest-derived cells entered the mouse gut. In contrast, cells did not migrate to these targets from presumptive aganglionic ls/ls bowel and quail crest-derived cells neither entered the ls/ls gut nor migrated through it. Laminin immunoreactivity was present in the backgrafts of murine colon and was far more abundant and widespread in those from ls/ls than in those from control animals. These data suggest that the presumptive aganglionic ls/ls bowel does not contain crest-derived cells because these cells, which are normal in ls/ls mice, do not enter it. This failure of colonization may be related to the premature formation of neurons outside the abnormal gut, a response that may be promoted by the excessive secretion of laminin by the ls/ls enteric mesenchyme.
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PMID:Inhibition of migration of neural crest-derived cells by the abnormal mesenchyme of the presumptive aganglionic bowel of ls/ls mice: analysis with aggregation and interspecies chimeras. 840 79

Increased fibre intake has been shown to reduce serum oestrogen concentrations. We hypothesized that fibre exerts this effect by decreasing the time available for reabsorption of oestrogens in the colon. We tested this in volunteers by measuring changes in serum oestrogen levels in response to manipulation of intestinal transit times with senna and loperamide, then comparing the results with changes caused by wheat bran. Forty healthy premenopausal volunteers were placed at random into one of three groups. The first group took senna for two menstrual cycles then, after a washout period, took wheat bran, again for two menstrual cycles. The second group did the reverse. The third group took loperamide for two menstrual cycles. At the beginning and end of each intervention a 4-day dietary record was kept and whole-gut transit time was measured; stools were taken for measurement of pH and beta-glucuronidase activity and blood for measurement of oestrone and oestradiol and their non-protein-bound fractions and of oestrone sulphate. Senna and loperamide caused the intended alterations in intestinal transit, whereas on wheat bran supplements there was a trend towards faster transit. Serum oestrone sulphate fell with wheat bran (mean intake 19.8 g day(-1)) and with senna; total- and non-protein-bound oestrone fell with senna. No significant changes in serum oestrogens were seen with loperamide. No significant changes were seen in faecal beta-glucuronidase activity. Stool pH changed only with senna, in which case it fell. In conclusion, speeding up intestinal transit can lower serum oestrogen concentrations.
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PMID:Lower serum oestrogen concentrations associated with faster intestinal transit. 925 10

Studies with pure cultures growing in laboratory media indicated that beta-glucuronidase expression of Escherichia coli S1 was considerably affected by starch added to the medium as the only carbon source. This result, which may be an aspecific modulation of enzyme expression, was independent of the starch molecular structure and effects were analogous for maize, rice, wheat or potato starches. It was observed that enzyme expression was little affected by the growth rate. The beta-glucuronidase activities of starch-grown bacteria found in the present study agree with those observed in animal and human models performed for in vivo evaluation of effects of dietary starch effects on gut microbial ecosystems.
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PMID:Effect of different starches on Escherichia coli (S1) beta-glucuronidase expression. 963 9

Several hydrolytic and reductive bacterial enzymes (beta-glucuronidase, GN; beta-glucosidase, GS; arylsulphatase, AS; azoreductase, AR; nitroreductase, NR) involved in production of mutagenic or genotoxic metabolites were measured in human colonic contents. Cell-associated AS and extracellular GS were approximately twice as high in the distal colon compared with the proximal bowel, while AR changed little throughout the gut. Measurements of these enzymes in faeces from seven healthy donors confirmed that the majority were cell-associated, and demonstrated high levels of inter-individual variability. NR decreased four-fold between the proximal and distal colon while extracellular GN was reduced by 50%. Most probable number (MPN) analysis on faeces obtained from six healthy donors showed that counts of intestinal bacteria producing GS and AR were c. 10(10) and 10(11)/g, respectively, in all samples tested. Numbers of GN- and AS-forming organisms were between two and three orders of magnitude lower. Inter-individual carriage rates of bacterial populations synthesising NR were highly variable. Screening of 20 pure cultures of intestinal bacteria, belonging to six different genera, showed that Bacteroides ovatus, in particular, synthesised large amounts of GS, whereas B. fragilis, B. vulgatus and Bifidobacterium pseudolongum formed the highest cell-associated levels of GN. In general, bifidobacteria and Lactobacillus acidophilus did not produce significant amounts of AR. All five clostridia studied (Clostridium bifermentans, C. septicum, C. perfringens, C. sporogenes and C. butyricum) produced NR and AR, as did the bacteroides (B. fragilis, B. ovatus and B. vulgatus). Escherichia coli and C. perfringens formed large amounts of NR. Levels of AS production were invariably low and few of the organisms screened synthesised this enzyme. In-vitro studies investigating the effect of intestinal transit time on enzyme production, in a three-stage (V1-V3) continuous culture model of the colon operated at system retention times (R) of either 31.1 or 68.4 h, showed that specific activities of GS were up to four-fold higher (V3) at R = 31.1 h. Bacteriological analysis demonstrated that representative populations of colonic micro-organisms were maintained in the fermentation system, and indicated that changes in GS activity were not related to numbers of the predominant anaerobic or facultative anaerobic species within the model, but were explainable on the basis of substrate-induced modulation of bacterial metabolism.
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PMID:Ecological and physiological studies on large intestinal bacteria in relation to production of hydrolytic and reductive enzymes involved in formation of genotoxic metabolites. 987 41

The effect of sucrose and resistant starch ('CrystaLean'--a retrograded, amylose starch) on human gut microflora and associated parameters was studied in human flora-associated (HFA) rats, colonized with microfloras from UK or Italian subjects, to determine whether such floras were affected differently by dietary carbohydrates. Consumption of the resistant starch diet resulted in significant changes in four of the seven main groups of bacteria enumerated. In both the UK and Italian flora-associated rats, numbers of lactobacilli and bifidobacteria were increased 10-100-fold, and there was a concomitant decrease in enterobacteria when compared with sucrose-fed rats. The induced changes in caecal microflora of both HFA rat groups were reflected in changes in bacterial enzyme activities and caecal ammonia concentration. Although it had little effect on caecal short-chain fatty acid concentration, CrystaLean markedly increased the proportion of n-butyric acid in both rat groups and was associated with a significant increase in cell proliferation in the proximal colon of the Italian flora-associated rats. CrystaLean appeared to play a protective role in the colon environment, lowering caecal ammonia concentration, caecal pH and beta-glucuronidase activity.
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PMID:Resistant starch modifies gut microflora and microbial metabolism in human flora-associated rats inoculated with faeces from Italian and UK donors. 1019 57

Two Escherichia coli strains in which alpha-amylase production differed were used to study in depth some characteristics related to beta-glucuronidase induction by starch. The beta-glucuronidase background activity in Luria broth medium was comparable for the two isolates, but only amylase positive S1 was able to grow on starch molecules supplied as the sole carbon source. In this case growth resulted at higher beta-glucuronidase levels (p < 0.01) with respect to basal activity and the induced expression was maximal (6.1-fold) when cultures reached the stationary phase. Growth in the presence of a protein synthesis inhibitor (chloramphenicol) was associated with a marked reduction of activity. The beta-glucuronidase activity of amylase negative M94 remained unchanged during starvation on starch medium, but an induced response was observed with methylumbelliferyl-glucuronide. These results further support the hypothesis that starch metabolism is involved in the complex beta-glucuronidase regulation of E. coli strains. This is relevant not only for basic research but also to investigating gut microbial enzymology.
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PMID:Implications of alpha-amylase production and beta-glucuronidase expression in Escherichia coli strains. 1051 Aug 69

Biotransformation of the phytoestrogen [14C]genistein was investigated in male and female rats by application of narrow-bore radio-HPLC-MSn (LCQ, Finnigan) to determine intermediates in metabolism. Urine contained five metabolites, Gm1-Gm5, 24 h after dosing by gavage with [14C]genistein (4 mg kg(-1)). Structural analysis following ESI revealed molecular ions [M+H]+ of m/z 447, 449, 273, and 271 for metabolites Gm2, Gm3, Gm5 and genistein, respectively and an [M-H]- of m/z 349 for Gm4. Metabolite structure was deduced by evaluation of product ion spectra derived from unlabelled and [14C]-labelled ions and sensitivity to treatment with beta-glucuronidase. These studies indicated identity of metabolites with genistein glucuronide (Gm2), dihydrogenistein glucuronide (Gm3), genistein sulphate (Gm4) and dihydrogenistein (Gm5). Detection of the beta-glucuronidase resistant major metabolite Gm1 by ESI was poor and so was analysed by negative ion APCI; this revealed a deprotonated molecular ion of m/z 165 which had chromatographic and mass spectral properties consistent with authentic 4-hydroxyphenyl-2-propionic acid, a novel metabolite of genistein. In vitro metabolism studies with anaerobic caecal cultures derived from male and female rats revealed metabolism of genistein to Gm1 via Gm5 and an additional metabolite (Gm6) which was identified from product ion spectra as 6'-hydroxy-O-desmethylangolensin. Biotransformation of genistein by both isolated hepatocytes and precision-cut liver slices was limited to glucuronidation of parent compound. Commonality of genistein metabolites found in rats with those reported in man suggest similar pathways of biotransformation, primarily involving gut micro-flora.
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PMID:Biotransformation of genistein in the rat: elucidation of metabolite structure by product ion mass fragmentology. 1062 5


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