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PubMedDate not supplied

The relative contributions of carboxylesterase and beta-glucuronidase in the formation of SN-38 in human colorectal tumours.

Irinotecan (CPT-11) is a prodrug that is used to treat metastatic colorectal cancer. It is activated to the topoisomerase poison SN-38 by carboxylesterases. SN-38 is subsequently metabolised to its inactive glucuronide, SN-38G, which can however be reactivated to SN-38 by beta-glucuronidase. The purpose of this study was to examine the role of carboxylesterases and beta-glucuronidase in the in vitro production of SN-38 in human colorectal tumours. The production of SN-38 from CPT-11 and SN-38G was measured by HPLC in human colorectal tumour homogenates. Carboxylesterase and beta-glucuronidase activities were found to be lower in tumour tissues compared to matched normal colon mucosa samples. In colorectal tumour, beta-glucuronidase and carboxylesterase-mediated SN-38 production rates were comparable at clinically relevant concentrations of SN-38G and CPT-11, respectively. Therefore, tumour beta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo, particularly during prolonged infusions of CPT-11.

Antineoplastic Agents, Phytogenic↗
PubMed1977

Hydrolysis of steroid glucuronides with beta-glucuronidase preparations from bovine liver, Helix pomatia, and E. coli.

We determined the enzymic activity of beta-glucuronidase preparations from bovine liver, Helix pomatia, and Escherischia coli with steroid glucuronides and nonsteroid glucuronides as substrates. We also studied the effect of Na2SO4 on the enzymic hydrolysis of several substrates with the three preparations of beta-glucuronidase. Na2SO4 increases the rate of hydrolysis of all substrates with beta-glucuronidase from bovine liver. Hydrolysis of a steroid glucoronide with beta-glucuronidase from Helix pomatia and E. coli is inhibited by Na2SO4. None of the three enzyme preparations gives complete hydrolysis of urinary steroid conjugates, because urine contains inhibitors, which can be removed by absorption chromatography of the urine on a column of neutral polystyrene resin Amberlite XAD-2. But when Amberlite XAD-2 is not used, hydrolysis of urinary glucuronides of androsterone, etiocholanolone, pregnanediol, estriol, and 17-hydroxycorticosteroids proves that, given an incubation time of 24 h, the beta-glucuronidase preparation from bovine liver, in the presence of Na2SO4, is suited for determining all of the above steroids except esriol; the preparation from Helix pomatia is good for determining estriol and 17-hydroxycorticosteroids; the preparation from E. coli is good for determining androsterone, 17-hydroxycorticosteroids, and especially estriol, the glucuronide, of which is maximally hydrolyzed in 2 h.

17-Hydroxycorticosteroids↗
PubMed1990

A new type of exo-beta-glucuronidase acting only on non-sulfated glycosaminoglycans.

Using chondroitin as a substrate, a new type of exo-beta-glucuronidase (EC 3.2.1.31) from rabbit liver was purified using a combination of ammonium sulfate fractionation, DEAE-cellulose chromatography, gel filtration on Sephracryl S-300, affinity chromatography through heparin-Sepharose CL-6B, and preparative polyacrylamide gel electrophoresis. This enzyme acts only on non-sulfated glycosaminoglycans and their oligosaccharides and was shown to be quite different from exo-beta-glucuronidase, which does act on p-nitro-phenyl-beta-D-glucuronide with regard to the following properties. 1) Neither sulfated glycosaminoglycanoligosaccharides nor p-nitrophenyl-beta-D-glucuronide were substrates for the enzyme. 2) The molecular weight was found to be about 130,000 by gel filtration, compared with a molecular weight of 280,000-300,000 for beta-glucuronidase, which acts on p-nitro-phenyl-beta-D-glucuronide. 3) The enzyme showed maximal activity at pH 5.0, compared with an optimum pH of 4.5 for beta-glucuronidase, which acts on p-nitro-phenyl-beta-D-glucuronide. 4) The enzyme showed maximal activity in 0.075 M NaCl but no activity above 0.25 M NaCl. 5) The enzyme was inhibited strongly by compounds bearing a sulfate group. 6) The enzyme did not react with an antibody against beta-glucuronidase acting on p-nitrophenyl-D-glucuronide. It is suggested that the enzyme may be involved in the catabolism of glycosaminoglycans, acting especially on chondroitin after the desulfation reaction and/or hyaluronic acid, but showing little involvement with the detoxification system.

Ammonium Sulfate↗
PubMed1990

[The changes of beta-glucuronidase in rabbit model with calcium bilirubinate stone].

The aim of the present study is to determine the beta-glucuronidase changes in bile and hepatobiliary tissue of rabbit model having pigment gallstone by means of biochemical and enzymehistochemical assay methods. The result showed both of the bacterial and non-bacterial beta-glucuronidase take part in the course of pigment gallstone formation. The bacterial beta-glucuronidase level increased quickly before the formation of gallstone, then decreased with control of bacterial infection. Non-bacterial beta-glucuronidase increased slowly in pro-formation stage of gallstone, then kept high level for long period of time. The relationship between beta-glucuronidase and pigment gallstone formation is also discussed.

Animals↗
PubMedDate not supplied

[Serum beta-glucuronidase activity in patients with epilepsy].

Little information is available on the effect produced by antiepileptic drugs on the serum beta-glucuronidase activity. According to recent findings, beta-glucuronidase serum levels are increased in patients with epilepsy just before the beginning of seizures and remain increased during several weeks; this it is suggested that determination of this enzyme could be important in the provision and the treatment of seizures. The purpose of the present study attempts to understand these changes. Our study was carried out on 49 adult healthy subjects and 48 adult epileptic patients receiving anticonvulsant therapies. Serum beta-glucuronidase activity was determined by a simplified procedure employing phenolphtalein glucuronic acid as substrate. The mean +/- SEM of serum beta-glucuronidase activity in treated patients (40.93 +/- 5.01 MSU/ml) was significantly higher than those of the healthy subjects (25.04 +/- 3.40 MSU/ml). In conclusion, the relationship between changes in serum enzyme activity, seizures and anticonvulsant therapies suggests that the determination of serum beta-glucuronidase activity presents a weak interest in predicting or treating seizures.

Adolescent↗
PubMed1979

The effect of beta-glucuronidase and chitinase on the cell wall of Aspergillus niger and Aspergillus fumigatus.

The effects of beta-glucuronidase and chitinase have been tested on the hydrolysis of the cell walls of the economically important fungi, Aspergillus niger and Aspergillus fumigatus. The extent of wall hydrolysis was measured by assaying for total reducing sugars, N-acetyl sugars and protoplast production. Maximum reducing sugar release was attained after 40 min incubation, both with beta-glucuronidase supplemented with chitinase and beta-glucuronidase alone, whereas N-acetyl sugar release reached a maximum at 80 min incubation. beta-Glucuronidase was effective in releasing protoplasts from both species of Aspergillus. This release was enhanced by adding chitinase to the incubation medium at 0 and 20 min, but with addition at 60, 80 and 100 min increase in protoplast yield was much reduced. The results of re-incubation experiments with chitinase suggest that this enzyme may in some way be inhibited during the later stages of incubation. Pronase used in combination with beta-glucuronidase slightly enhanced protoplast release.

Aspergillus fumigatus↗
PubMed1985

Egasyn, a protein which determines the subcellular distribution of beta-glucuronidase, has esterase activity.

The glycoprotein egasyn complexes with and stabilizes precursor beta-glucuronidase in microsomes of several mouse organs. Several observations indicate egasyn is, in addition, an esterase. Liver homogenates of egasyn-positive strains have specific electrophoretically separable esterases which are absent in egasyn-negative mice. These esterases react with anti-egasyn serum. A specific esterase was likewise complexed with immunopurified microsomal beta-glucuronidase. The esterases were, like egasyn and microsomal beta-glucuronidase, concentrated in the microsomal subcellular fraction. Egasyn which is not bound to beta-glucuronidase, which represents 80-90% of total liver egasyn, is not complexed with other liver proteins. Egasyn, therefore, specifically stabilizes beta-glucuronidase in microsomes. The esterase activity is inhibited by bis-p-nitrophenyl phosphate indicating it is a carboxyl esterase. Several possible functions of egasyn-esterase activity are discussed.

Animals↗
PubMed1976

Beta-glucuronidase activity of Yoshida ascites hepatomas of different drug-sensitivity and its change after treatment of host rats with various anticancer agents.

Change in beta-glucuronidase activity of six Yoshida ascites hepatomas was examined after treatment of host rats with one of 12 anticancer agents. The hepatomas, AH-66F, AH-130, AH-109A, AH-60C, and AH-44, in decreasing order showed more or less distinct increase in beta-glucuronidase activity after treatment of the rats with Nitromin, Endoxan, 864-T, Carbazilquinone, Mitomycin-C, Toyomycin, Daunomycin, Neocarzinostatin, vincristine sulfate, 5-fluorouracil, or cytosine arabinoside only when the cytological effect was positive. Moreover, degree of the increase was generally correlated with that of cytological effect. Bleomycin was ineffective either enzymically or cytologically. AH-66 was insensitive to any of the agents tested in increasing beta-glucuronidase activity and showed only a very slight cytological response to some of the agents. Acid deoxyribonuclease behaved like beta-glucuronidase but to a lesser extent. The above order of drug sensitivity of the hepatomas was not in parallel with that of normal beta-glucuronidase level, which also did not correlate with the life span of host rats.

Animals↗
PubMed1984

[beta-Glucuronidase in human maxillary sinus and lung cancers: elevation of activity level and appearance of phosphorylated variant forms].

beta-Glucuronidase from human maxillary sinus and lung cancers and from uninvolved tissues was studied. An elevation of beta-glucuronidase activity was observed in cancerous tissues as compared with the corresponding uninvolved tissues, and this increase was significant in adenocarcinoma and squamous cell carcinoma of the lung (p less than 0.01). beta-glucuronidase preparations purified from adenocarcinoma and large cell carcinoma of lung and from normal lung showed similar kinetic properties and antigenicity. beta-Glucuronidase from lung adenocarcinoma showed considerable negative charge heterogeneity in the pI range from 4.2 to 6.2 in an experiment involving isoelectric focusing on polyacrylamide gel. Similar charge heterogeneity was observed in the enzyme from lung large cell carcinoma. Upon treatment of the adenocarcinoma enzyme with exogenous alkaline phosphatase or endoglycosidase H, the heterogeneous variant forms of the tumor enzyme appeared to partly or completely lose their negative charge and to be converted into forms similar to those of the normal lung enzyme. An experiment on the labeling of beta-glucuronidase with [32P]-phosphoric acid provided further evidence that the acidic variants found in lung cancers are extensively phosphorylated forms of the enzyme.

Adenocarcinoma↗
PubMed1983

Changes of the activity of acid phosphatase and beta-glucuronidase in isolated platelets of whole-body irradiated rats.

In the work presented here we paid our attention to studying changes of the activity of two lysosomal enzymes-acid phosphatase and beta-glucuronidase in platelets after whole-body irradiation and application of certain clinically applied antifibrinolytics (Antilysin Spofa and epsilon-aminocaproic acid) on the activity of these enzymes in isolated platelets. From the results it is obvious that the activity of acid phosphatase and beta-glucuronidase increases in platelets of irradiated rats with a maximum on the 11th day after irradiation. In the same time interval after irradiation the most remarkable thrombocytopenia was observed. The application of Antilysin or EACA to intact, non-irradiated rats affects remarkably neither the activity of the followed enzymes nor the count of platelets. A statistically significant thrombocytopenia, in a comparison with controls was found in whole-body irradiated rats who received EACA or Antilysin. The postirradiation increase of the level of acid phosphatase in platelets exerts a similar character in rats who received EACA or Antilysin as in those who were only irradiated with a difference that the increase of the level of this enzyme was essentially lower in all the time intervals of interest. The beta-glucuronidase level in platelets of rats, who received EACA, was essentially unchanged as compared to controls. The application of Antilysin altered remarkably the level of beta-glucuronidase in platelets of whole-body irradiated rats in a comparison with a level of this enzyme in platelets of rats who received no Antilysin. Most remarkable changes were observed in latter time intervals (11th and 15th day) when the beta-glucuronidase level in platelets of rats after the application of Antilysin was remarkably higher than that in solely irradiated rats.

Acid Phosphatase↗
PubMed1984

Studies of the catalytic mechanism of microsomal UDP-glucuronyltransferase. Alpha-glucuronidase activity and its stimulation by phospholipids.

The rate at which a specific, purified form of microsomal UDP-glucuronyltransferase (designated as the GT2P type of this enzyme) catalyzes the hydrolysis of UDP-glucuronic acid was measured with pure, delipidated enzyme and enzyme reconstituted with different lysophosphatidylcholines. This activity of the GT2P type of UDP-glucuronyltransferase is referred to as alpha-glucuronidase activity. For delipidated enzyme, the rate of hydrolysis of UDP-glucuronic acid catalyzed by GT2P extrapolated to infinite concentrations of UDP-glucuronic acid was 1 X 10(-9) mol/min/mg of protein. This compares with a rate of glucuronidation of p-nitrophenol of 96 X 10(-9) mol/min/mg of enzyme, for delipidated enzyme. Addition of oleoyl- or myristoyllysophosphatidylcholine to GT2P did not affect the alpha-glucuronidase activity significantly. This activity was stimulated, however, in the presence of compounds that bind at the aglycone site but that do not undergo glucuronidation. alpha-Glucuronidase activity extrapolated to infinite concentration of UDP-glucuronic acid was 4.0 X 10(-9) mol/min/mg for delipidated enzyme assayed in the presence of less than saturating concentrations of p-nitrophenyl phenyl ether. Moreover, when the aglycone site of GT2P was occupied by ethers, the alpha-glucuronidase activity of this enzyme was enhanced by addition of phospholipids to delipidated enzyme. The extent of activation of the alpha-glucuronidase activity of GT2P, when the aglycone site was occupied, depended on the acyl chain of the lipid added to delipidated enzyme. These data indicate that the GT2P form of UDP-glucuronyltransferase catalyzes the hydrolysis of UDP-glucuronic acid at a significant rate and that lysophosphatidylcholines can influence this rate.

Animals↗
PubMed1982

Immunocytochemical localization of beta-glucuronidase in the male rat preputial gland.

Present knowledge of the in situ intracellular localization of acid hydrolases is mainly based on enzyme-cytochemical observations. In the preputial gland cells beta-glucuronidase and acid phosphatase were thus demonstrated in lysosome-like secretory granules and the GERL system. We applied immunocytochemistry to localize beta-glucuronidase at the earliest sites of biosynthesis. Lysosomal beta-glucuronidase was purified from preputial gland by column chromatography and SDS gel electrophoresis. Antibodies were raised in rabbit and affinity-purified preparations were used for immunocytochemistry on thin frozen sections of perfusion fixed preputial glands. Indirect procedures were applied with a second antibody labelled with rhodamine for fluorescence, and 5 or 8 nm protein A-gold probes for electron microscopy. beta-Glucuronidase occurred in all cells, except for the precursor cells, and was localized throughout the endoplasmic reticulum and perinuclear space, in all Golgi cisternae and storage granules, and in autophagic vacuoles. Thus in the preputial gland cell, beta-glucuronidase is present in both the lysosomal and the secretory system.

Animals↗
PubMed1982

Effect of beta-glucuronidase inhibitor on azoxymethane-induced colonic carcinogenesis in rats.

In this study of the role of microfloral beta-glucuronidase in colonic carcinogenesis, the effect of beta-glucuronidase inhibitor was evaluated. Starting at 5 weeks of age, male Donryu rats were fed either a semisynthetic diet or the same diet containing 0.1% beta-glucuronidase inhibitor as N-cyclohexyl-5-O-acetyl-2,4-O-p-methoxybenzylidene) -D-glucaro-1-amide-6,3-lactone (C-GAL). All animals were given s.c. injections of 7.4 mg azoxymethane (AOM) per kg body weight once a week for 11 weeks and followed for an additional 20 weeks. Most animals receiving the colonic carcinogen developed tumors in the colon, and a few also developed tumors in the small intestine. However, the number of tumors in the large intestine of the rats given C-GAL at the same time as AOM was significantly lower than in the control rats, especially in the proximal half of the colon, but those given C-GAL after AOM treatment had almost the same number of colon tumors as did the controls. It is concluded that, since bacterial beta-glucuronidase activity in the feces of rats given 0.1% C-GAL was significantly inhibited, intestinal microfloral beta-glucuronidase may play an important role in colonic carcinogenesis caused by AOM.

Animals↗
PubMed1982

Biliary control of beta-glucuronidase activity in the luminal contents of the rat ileum, cecum, and rectum.

The effect of bile exclusion on intestinal beta-glucuronidase activity was studied in the rat. Bile exclusion dramatically decreased the bacterial beta-glucuronidase activity in the cecum and rectum but did not affect the normal low level in the ileum. Thus, bile flow may be the most important factor in modulating beta-glucuronidase activity in the rat large bowel. Dietary substances which can alter bile flow may thus have effects on intestinal bacterial beta-glucuronidase activity. Effects of diet on colon cancer might therefore be explicable in terms of altered bile flow rather than altered bacterial beta-glucuronidase induction.

Animals↗
PubMed1981

Genetic determination of kinetic parameters in beta-glucuronidase induction by androgen.

A regulatory locus, Gus-r, determines the rate and extent of androgen inducibility of beta-glucuronidase in mouse kidney epithelial cells. The kinetics of induction are strikingly similar when enzyme concentration, rates of enzyme synthesis, and beta-glucuronidase mRNA are measured. After an initial lag period the accumulation of mRNA activity obeys simple turnover kinetics defined by ka, a zero order rate constant for acquisition of mRNA activity, and kb, a first order rate constant for loss of activity. The induced state is approached with a half-life of 8-9 days in the presence of testosterone and decays rapidly in the absence of testosterone. The half-life of both beta-glucuronidase and its mRNA appear to be much shorter, approximately 1-2 days, in both the presence and absence of testosterone. We conclude that the material accumulating in response to androgen is probably a transcriptionally activated state of beta-glucuronidase chromatin. Comparison of the a and b alleles of Gus-r, and a newly described h allele, shows that Gus-r determines ka and the duration of the lag period, but not kb, which was genetically invariant. The changes in ka and the duration of the lag are inversely related, suggesting that they reflect a common step during induction. These results are most simply accounted for by assuming that beta-glucuronidase regions in chromatin react with many molecules of androgen receptor protein-testosterone complex and that the rate of transcription is a function of the number of molecules bound. The lag period, then, reflects a requirement that a minimum number of sites must be occupied before transcription begins to increase. We suggest that the Gus-r locus determines the accessibility or affinity of androgen receptor complexes to chromatin. Because of this Gus-r determine both ka and the duration of the lag and the two parameters are inversely related to each other.

Amanitins↗
PubMed1980

[Interactions between desoxycholic acid glucuronides and glucuronidase (author's transl)].

It has been found that desoxycholic acid-3- (1), -12- (2) and -3,12-bis-beta-D-glucuronide (3) exert a potent allosteric effect on the beta-glucuronidase activity, which results in non-competitive inhibition of this enzyme in the pH range from 4.5 to nearly 5.5, and in its activation in the pH range from 6 to 7.4. Desoxycholic acid as well as as glycodesoxycholic acid and taurodesoxycholic acid caused a slight activation of beta-glucuronidase in the total pH range from 4.5 to 7.4. The dependence of these effects upon the pH value and the amount of the respective desoxycholic acid derivative used was demonstrated by the example of the cleavage of phenolpthalein-beta-D-glucuronide by beta-glucuronidase in the presence of the desoxycholid acid derivatives. The results obtained permit to interpret the cleavage of 1 by beta-glucuronidase. The cleavage of 1 by beta-glucuronidase is sufficiently rapid to use 1 as a CMT-selectin in the cancer multistage therapy according to Ardenne [1, 2, 5]. In contrast, no cleavage was observed in 2 and 3. To follow the cleavage of 1, a simple method has been developed which permits to determine mixtures of 1 and desoxycholic acid.

Animals↗
PubMed1995

A pseudodeficiency allele (D152N) of the human beta-glucuronidase gene.

We present evidence that a 480G-->A transition in the coding region of the beta-glucuronidase gene, which results in an aspartic-acid-to-asparagine substitution at amino acid position 152 (D152N), produces a pseudodeficiency allele (GUSBp) that leads to greatly reduced levels of beta-glucuronidase activity without apparent deleterious consequences. The 480G-->A mutation was found initially in the pseudodeficient mother of a child with mucopolysaccharidosis VII (MPSVII), but it was not on her disease-causing allele, which carried the L176F mutation. The 480G-->A change was also present in an unrelated individual with another MPSVII allele who had unusually low beta-glucuronidase activity, but whose clinical symptoms were probably unrelated to beta-glucuronidase deficiency. This individual also had an R357X mutation, probably on his second allele. We screened 100 unrelated normal individuals for the 480G-->A mutation with a PCR method and detected one carrier. Reduced beta-glucuronidase activity following transfection of COS cells with the D152N cDNA supported the causal relationship between the D152N allele and pseudodeficiency. The mutation reduced the fraction of expressed enzyme that was secreted. Pulse-chase experiments indicated that the reduced activity in COS cells was due to accelerated intracellular turnover of the D152N enzyme. They also suggested that a potential glycosylation site created by the mutation is utilized in approximately 50% of the enzyme expressed.

Alleles↗
PubMed1995

Effect of beta-glucuronidase on urinary benzodiazepine concentrations determined by fluorescence polarization immunoassay.

In samples from patients treated with oxazepam, beta-glucuronidase increased the immunoreactivity of urinary benzodiazepines analyzed by fluorescence polarization immunoassay (FPIA). Increasing concentrations of beta-glucuronidase added to samples from drug-free controls did not influence the results. In the absence of beta-glucuronidase, 22 of 35 samples from patients undergoing detoxification gave positive results at a cutoff concentration of 200 micrograms/L. Pretreatment with beta-glucuronidase increased the number of drug-positive samples to 33. The drug-negative samples were obtained from two patients who had been oxazepam-free for at least 1 week. Thus, beta-glucuronidase can be used to increase the sensitivity of the urinary benzodiazepine FPIA without reducing the specificity of the method.

Benzodiazepines↗