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)

To test the hypothesis that enhanced intestinal absorption of bilirubin may contribute to prolonged nonconjugated hyperbilirubinemia in human milk-fed infants, we studied a cross-section of 36 healthy infants and mothers. Milk from mothers and serum from infants were collected at 16.3 +/- 2.4 days. Milk was studied for its effect on the absorption of bilirubin labeled with carbon 14 in rats and compared with buffer and iron-fortified infant formula (Similac With Iron). The percentage of a 1 mg bilirubin dose absorbed by the rat was 25.29 +/- 4.0% when it was administered into the duodenum with buffer, 4.67 +/- 2.4% with Similac formula, and 7.7 +/- 2.9% with human milk. Linear regression analysis, using the infant's serum nonconjugated bilirubin level as the dependent variable and the percentage of (14C)bilirubin absorbed by the rat with the corresponding mother's milk as the independent variable, revealed a significant correlation (r = 0.40; p = 0.016). Inspection of the data suggested that absorptive permissiveness correlated closely with infant serum bilirubin values greater than 24 mumol/L (1.4 mg/dl) (r = 0.55; p = 0.007), whereas in those with bilirubin values less than or equal to 24 mumol/L, there was no apparent correlation. Milk was also analyzed for beta-glucuronidase, nonesterified fatty acids, and the ability to inhibit glucuronosyltransferase activity of rat liver microsomes in vitro, none of which correlated with the infant's serum bilirubin. These data support the theory that enhanced intestinal absorption of bilirubin contributes to the jaundice associated with breast-feeding.
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PMID:Enterohepatic circulation of nonconjugated bilirubin in rats fed with human milk. 199 86

Activities of glucuronosyltransferase, sulfotransferase, glutathione S-transferase, beta-glucuronidase and sulfatase were determined in microdissected samples of periportal and pericentral sublobular regions from four human livers obtained at immediate autopsy. New methods are presented for the microdetermination of sulfotransferase and sulfatase activities in microdissected samples weighing 0.1 to 4 micrograms dry weight using umbelliferone and 4-methylumbelliferone sulfate as substrates. The three transferases were distributed heterogeneously across the liver lobule. Glucuronosyltransferase and glutathione S-transferase were localized predominantly in pericentral regions. In contrast, sulfotransferase activity was greater in periportal than pericentral regions. Average activities for glucuronosyltransferase and sulfotransferase were 23, and 50 mumoles X gm dry wt-1 X hr-1, respectively, in periportal regions, and 34 and 38 mumoles X gm dry st-1 X hr-1, respectively, in pericentral regions. Activities of glutathione S-transferase were considerably higher than those of the other transferases and were 8.3 mmoles X gm dry wt-1 X hr-1 in periportal areas and 12.2 mmoles X gm dry wt-1 hr-1 in pericentral areas. The two hydrolases studied, beta-glucuronidase and sulfatase, were evenly distributed across the liver lobule. The presence of significant hydrolase and transferase activities in both zones of the liver lobule supports the idea that net production of both sulfate and glucuronide conjugates may be influenced by futile cycling of conjugation-deconjugation reactions in both zones of the liver. Based on enhanced formation of sulfate but not glucuronide conjugates in homogenates of human liver treated with inhibitors of the hydrolases, it is suggested that futile cycling is more pertinent to the regulation of sulfation than glucuronidation.
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PMID:Sublobular distribution of transferases and hydrolases associated with glucuronide, sulfate and glutathione conjugation in human liver. 308 5

The net glucuronidation of bilirubin (BR) has been determined in inbred and outbred rat strains and their subpopulations with similar glucuronosyltransferase (EC 2.4.1.17) activity but with different levels of beta-glucuronidase (beta G) (EC 3.2.1.31), or in which the level of beta G activity was reduced with D-glucaro-1,4-lactone. These studies demonstrated that outbred rat strains consist of two subpopulations that differ approximately 1.5- to two-fold in serum and liver beta G activity. Evidence is presented indicating that owing to its compartmentalization the lysosomal beta G, unlike the corresponding microsomal enzyme, is neither inhibited by glucarolactone nor accessible for hydrolysis of newly synthesized glucuronides. The ratio of glucuronidated to unconjugated BR 15 min after injection of albumin-bound BR into the tail vein appears to correlate negatively with the liver microsomal beta G activity. The results may be relevant to the relative risk to toxins, including carcinogens, and to their reduction by dietary intervention.
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PMID:Net glucuronidation in different rat strains: importance of microsomal beta-glucuronidase. 311 56

Rates of hydrolysis of 3-hydroxybenzo[a]pyrenyl glucuronide by microsomal beta-glucuronidase from rat liver were 397 +/- 17 nmol/min per g protein and were half-maximal with about 100 microM substrate. Treatment of rats with phenobarbital or 3-methylcholanthrene, which elevates activities of glucuronosyltransferase(s), lowered rates of hydrolysis of benzo[a]pyrene glucuronide by 25%. Hydrolysis of the glucuronide by microsomal beta-glucuronidase was stimulated by micromolar concentrations of calcium in the range existing in cytosol of hepatocytes (apparent Km approximately 0.2 microM). Thus, humoral factors that change intracellular concentrations of free calcium may alter the production and export of glucuronides of benzo[a]pyrene metabolites from the liver.
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PMID:Stimulation of 3-benzo[a]pyrenyl glucuronide hydrolysis by calcium activation of microsomal beta-glucuronidase. 397 4

Dissociated sponge cell system has proved to be a useful model to study the process of cell aggregation both on cellular and subcellular level. The purpose of this review is to discuss recent results obtained from experiments with the marine sponge Geodia cydonium. Dissociated cells form functional aggregates during a process which can be sub-divided into three phases: first, formation of small primary aggregates in the presence of Ca2+; second, formation of secondary aggregates in the presence of an aggregation factor and third, reconstitution of a functional system of water-containing channels by rearrangement in the secondary aggregates. On subcellular level a series of macromolecules are known which are involved in the control of aggregation and separation of sponge cells: Aggregation factor, aggregation receptor, anti-aggregation receptor, beta-glucuronidase, beta-glucuronosyltransferase, beta-galactosyltransferase, beta-galactosidase and a lectin. These components might be linked in the following sequence: (a) Activation of the aggregation receptor by its enzymic glucuronylation; (b) Adhesive recognition of the cells, mediated by the aggregation factor and the glucuronylated aggregation receptor; (c) Inactivation of the aggregation receptor by its deglucuronylation with the membrane-associated beta-glucuronidase; (d) Cell separation due to either the loss of the recognition site (glucuronic acid) of the aggregation receptor for the aggregation factor or to an inactivation of the aggregation factor by the anti-aggregation receptor. The activity of the anti-aggregation receptor is most likely controlled by the Geodia lectin. The events leading to cell-cell recognition cause a change in the following metabolic events: Increase of oxygen uptake, decrease of cyclic AMP level, increase of cyclic GMP level and stimulation of programmed syntheses.
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PMID:Sponge cell aggregation. 624 12

The aim of these studies was to characterize the glucuronide conjugates of digitoxin and digitoxigenin monodigitoxoside (DMD) produced by liver microsomes from the dog with respect to hydrolysis by beta-glucuronidase and to behavior on HPLC. These results have been compared with studies of conjugates produced by liver microsomes from the rat. Glucuronidation was similar with both substrates with dog microsomes, whereas rat microsomes formed the glucuronide with DMD but not with digitoxin. The DMD glucuronide from both species was completely hydrolyzed by beta-glucuronidase, but no hydrolysis of digitoxin glucuronide was detected. The digitoxin glucuronide was hydrolyzed by a buffer at pH 1.5 but not at pH 10. After acid hydrolysis, the major products appear to be digitoxigenin and DMD glucuronide. These results suggest that glucuronidation of certain drugs by the dog is quite different from that of other species and that the dog may be the only species that possesses a glucuronosyltransferase capable of forming a glucuronide conjugate with digitoxin. The dog also has a glucuronosyltransferase, similar to that in the rat, which is responsible for glucuronidation of DMD. Whether this represents a single glucuronosyltransferase or two different enzymes remains to be elucidated.
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PMID:Formation of a beta-glucuronidase-resistant glucuronide conjugate of digitoxin by dog liver microsomes. 790 97

Mouse colon adenocarcinoma Co38 is widely used as a screening model for human colon tumors. To understand better the influence of tumor size on the main drug-metabolizing enzyme systems, we tested 15 mouse Co38 tumors at different sizes. The average weight was 917 +/- 444 mg (range, 300-1,400 mg). Cytochromes P-450 (1A1/1A2, 2B1/B2, 2C8-10, 2E1, 3A4), epoxide hydrolase (EH), and glutathione-S-transferases (GST-alpha, -mu, and -pi) were assayed by immunoblotting. The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: 1-chloro-2,4-dinitrobenzene-GST (CDNB-GST), selenium-independent glutathione peroxidase (GPX), 3,4-dichloronitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), total glutathione (GSH), uridine diphosphate-glucuronosyltransferase (UDP-GT), beta-glucuronidase (beta G), sulfotransferase (ST), and sulfatase (S). Our results showed the absence of all probed P-450s and EH in Co38 tumors. No relationship was found between the Co38 tumor weights and GPX, GST-alpha, and EA-GST (regression analysis). However, a significant correlation was found between the tumor weights and all other enzymes investigated. For certain enzymes or cofactors, a linear decrease (P < 0.05) was observed as a function of tumor weight (CDNB-GST, DCNB-GST, GST-mu, GST-pi, GSH, and beta G). Other enzymatic activities (UDP-GT, S, and ST) were found to decrease in medium-size tumors and to increase in large tumors (P < 0.05; quadratic correlation). These data demonstrate that the expression of many drug-metabolizing enzyme systems is altered during tumor growth and suggest that tumoral response to chemotherapy could be altered as a function of tumor size.
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PMID:Influence of tumor size on the main drug-metabolizing enzyme systems in mouse colon adenocarcinoma Co38. 792 60

Irinotecan (CPT-11 [Camptosar]), a semisynthetic derivative of the plant alkaloid camptothecin, is bioactivated by carboxylesterases (EC3.1.1-) to the topoisomerase I inhibitor SN-38, a minor metabolite. Bioactivation of intravenously administered irinotecan by carboxylesterases occurs predominantly in the liver. Two human carboxylesterase isoforms responsible for SN-38 formation have been characterized. At relevant hepatic irinotecan concentrations up to 12 micrograms/mL, a low-Km isoform is responsible for irinotecan bioactivation. High concentrations of drugs commonly coadministered with irinotecan do not inhibit carboxylesterase activity. Intestinal carboxylesterases can also generate SN-38, followed by subsequent oral absorption. A second major polar metabolite of irinotecan, aminopentanecarboxylic acid (APC), is the product of CYP3A4-mediated oxidation of the terminal piperidine ring. APC is 100-fold less active than SN-38 as a topoisomerase I inhibitor and is a relatively weak inhibitor of acetylcholinesterase. SN-38 is eliminated mainly through conjugation by hepatic uridine glucuronosyltransferase (UGT*1.1), the same isoezyme responsible for glucuronidation of bilirubin. Grade 4 irinotecan-related toxicity (ie, neutropenia, diarrhea) has recently been reported in two patients with deficient UGT*1.1 activity. SN-38 glucuronide (SN-38G), which has only 1/100th the antitumor activity of SN-38, is actively secreted into the bile by a canalicular multispecific organic anion transporter. Deconjugation of SN-38G to SN-38 by beta-glucuronidase produced by the intestinal flora may contribute to enterohepatic recirculation of SN-38 and delayed intestinal toxicity.
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PMID:Pharmacology of irinotecan. 972 89

The effect of adjuvant-induced arthritis on hepatic microsomal glucuronidation was studied in the rat. Arthritis was induced by injection of Mycobacterium butyricum suspended in liquid paraffin. Vmax and the Michaelis-Menten constant values for the in vitro glucuronidation of R- and S-ketoprofen, acetaminophen, and diflunisal by liver microsomes obtained from control and adjuvant-induced arthritic rats were compared. In addition, uridine 5'-diphosphate-glucuronosyltransferase activity toward bilirubin and p-nitrophenol, as well as levels of cytochrome P-450 and beta-glucuronidase were determined in these microsomal preparations. Adjuvant-induced arthritis resulted in a significant reduction in hepatic cytochrome P-450 levels and in p-nitrophenol glucuronidation (5.65 +/- 0.40 versus 2.58 +/- 0.27 micromol.min/mg protein in control and arthritic rats, respectively, mean +/- S.E.M.). Glucuronidation of bilirubin and beta-glucuronidase activities in liver microsomes and in plasma were not affected by adjuvant-induced arthritis. Vmax (nmol/min/mg protein) for the formation of R-ketoprofen glucuronide, S-ketoprofen glucuronide, diflunisal phenolic glucuronide, and diflunisal acyl glucuronide was significantly decreased in arthritic rats (0.68 +/- 0.10, 0.77 +/- 0. 12, 0.044 +/- 0.005, 0.26 +/- 0.03, respectively) compared with control rats (1.45 +/- 0.04, 1.60 +/- 0.04, 0.087 +/- 0.008, 0.46 +/- 0.04, respectively). Glucuronidation of p-nitrophenol, ketoprofen and diflunisal, substrates which seem to be at least partly glucuronidated in the rat by isoenzymes of the UGT2B subfamily, was impaired in adjuvant-induced arthritis. Glucuronidation of bilirubin and acetaminophen, substrates of UGT1- isoenzymes, was not affected by adjuvant-induced arthritis. It seems, therefore, that adjuvant-induced arthritis in the rat leads to impaired glucuronidation of substrates of the UGT2B subfamily.
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PMID:Glucuronidation of R- and S-ketoprofen, acetaminophen, and diflunisal by liver microsomes of adjuvant-induced arthritic rats. 988 6

Human uridinediphosphate-glucuronosyltransferase 1A1 (UGT1A1) was expressed in Salmonella typhimurium TA1535 cells by transfection of the cells with plasmids carrying the UGT1A1 cDNA. UGT1A1 cDNA was isolated by a polymerase chain reaction from human liver total RNA and was inserted into the pSE420 plasmid, linked to the trc promoter and terminator. The plasmid thus constructed was introduced into Salmonella TA1535 cells. The expression of human UGT1A1 protein was confirmed by Western blot analysis. The maximal expression was observed at 24 h after the addition of isopropyl-beta-D-thiogalactopyranoside, an inducer. However, the bilirubin conjugation activity of the membrane fraction from the Salmonella cells was not detectable. When a beta-glucuronidase inhibitor such as saccharic acid 1,4-lactone, glycyrrhizin or 1-naphtyl-beta-D-glucuronide was added to the reaction mixture, the bilirubin conjugation activity of the human UGT1A1 was detected. When geniposide was added to the reaction mixture, the bilirubin conjugation activity of UGT1A1 was not seen. Taking these results into account, the established Salmonella strain possesses the beta-glucuronidase activity. Since the beta-glucuronidase activity of the Salmonella was lower than that of E. coli, it was concluded that Salmonella seemed to be a good host to express UGT protein. This is the first study to demonstrate the establishment of a bacterial strain expressing native human UGT protein showing catalytic activity.
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PMID:Establishment of Salmonella strain expressing catalytically active human UDP-glucuronosyltransferase 1A1 (UGT1A1). 1082 Nov 20


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