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)

The authors studied combined effect of aniline (20 mg/kg for a period of 4 weeks in drinking water) and nitrosodimethylamine (NDMA) (30 mg/kg, a single intragastric dose) on the activity of enzymes of different subcellular structures: endoplasmic reticulum (cytochromes P450, B5, acetylesterase), mitochondria (malate dehydrogenase) and the content of N-acetylneuraminic acid in rat liver and of lysosomes (beta-glucuronidase, beta-galactosidase). The combined action of NDMA and aniline was accompanied by more pronounced changes in the indices under investigation than isolated administration of the given chemical substances. The most pronounced aggravation of the unfavourable changes was observed in the activity of enzymes connected with the processes of oxidation and energy supply to the cell (malate dehydrogenase) and the metabolism of glucuronides (beta-glucuronidase) as well as in the content of N-acetylneuraminic acid. This may be connected with the modifying effect of aniline on the toxic effect of NDMA.
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PMID:Combined effect of nitrosodimethylamine and aniline on the enzyme systems of subcelluar structures. 680 54

The effects of indium-chloride (InCl3) on hepatocyte structure and function were studied in male rats injected with doses of 0, 10, 20, or 40 mg of InCl3/kg and killed after 16 hours. Fragmentation and degranulation of the rough endoplasmic reticulum and increased numbers of In- and Fe-containing autophagic lysosomes were the most marked cellular changes observed by electron microscopy. Morphometric analyses of hepatocytes disclosed a maximal 4-fold increase in the volume density of the lysosome compartment and a 2-fold decrease in the volume density of the vacuole compartment. Surface densities of the mitochondrial cristae and rough endoplasmic reticulum were increased by 1.5-fold, whereas the surface densities of the smooth endoplasmic reticulum showed a maximal increase of 7-fold. These structural changes were associated with inhibition of microsomal aniline hydroxylase by as much as 50% and ethoxyresorufin-O-deethylase by as much as 30% but no change in aminopyrine demethylase activity. Microsomal acid phosphatase activity was also decreased to 74% of control, whereas beta-glucuronidase was unchanged. Mild inhibition of mitochondrial respiratory function but no changes in marker enzyme activities were noted. Lysosomal marker enzyme activities were also unaffected, with the exception of acid phosphatase, which was maximally decreased to 55% of control. The data indicate that acute InCl3 injection produces a primary effect on hepatocyte endoplasmic reticulum structure with attendant changes in both heme- and nonheme-dependent biochemical functions. These findings suggest that altered regulation of hepatic microsomal heme metabolism by indium and other metals occurs as part of a general process involving degradative changes in the endoplasmic reticulum structure due to membrane damage with subsequent lysosomal autophagy of nonfunctional components.
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PMID:Alteration of hepatic microsomal structure and function by indium chloride. Ultrastructural, morphometric, and biochemical studies. 683 87

The HT29R colonic adenocarcinoma xenograft has been shown to be rich in the enzyme beta-glucuronidase. Experiments in rodent systems have demonstrated a marked anti-tumour effect of the drug aniline mustard (AM) on tumours with high levels of this enzyme (e.g. the plasmacytomas PC5 and PC6). We have found that AM is no more effective than its analogue paramethyl aniline mustard (PMAM) or other alkylating agents against the HT29R xenograft. Amongst the possible explanations for this may be: (1) The wide shoulder on the cell-survival curve shown for exposure to alkylating agents of HT29R in vivo. (2) Lack of correlation between physiological availability of beta-glucuronidase and the high levels measured by the standard assay. (3) Increased beta-glucuronidase levels in host mouse marrow, making the latter potentially more susceptible to AM damage.
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PMID:Response of a high-glucuronidase human tumour xenograft to aniline mustard. 705 62

To understand the factors involved in the enhanced testicular toxicity of di(2-ethylhexyl)phthalate (DEHP) in developing animals, po doses of 50, 100, 250 or 500 mg DEHP/kg were administered to 25-d-old albino rats for 30 consecutive days. Activities of testicular and hepatic cytochrome P-450 enzymes were determined. A dose-dependent increase in the activities of lactate dehydrogenase and gamma-glutamyl transpeptidase and a decrease in sorbitol dehydrogenase was observed in the testes. The activity of beta-glucuronidase increased at dosages of 250 and 500 mg/kg, while acid phosphatase decreased. Testes had marked destructive changes in the advanced germ cell layers at dosages of 250 and 500 mg/kg, which supports biochemical studies indicating that DEHP interacts with the maturation process of the testes. The dose-dependent decrease in hepatic cytochrome P-450 levels and the activities of ethylmorphine N-demethylase and aniline hydroxylase suggest that impaired metabolism of DEHP could lead to higher amounts of the diester or its metabolites reaching the testes; this may result in enhanced vulnerability of the testes to DEHP in developing animals.
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PMID:Testicular toxicity of Di(2-ethylhexyl)phthalate in developing rats. 854 Feb 15

Artificial recombinant receptors may be useful for selectively targeting imaging and therapeutic agents to sites of gene expression. To evaluate this approach, we developed transgenes to express highly on cells a single-chain antibody (scFv) against the hapten 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one (phOx). A phOx enzyme conjugate was created by covalently attaching phOx molecules to polyethylene glycol (PEG)-modified beta-glucuronidase. Cells expressing phOx scFv but not control scFv receptors were selectively killed after exposure to ss-glucuronidase derivatized with phOx and PEG (phOx-beta G-PEG) and a glucuronide prodrug (p-hydroxy aniline mustard beta-D-glucuronide, HAMG) of p-hydroxyaniline mustard. Targeted activation of HAMG produced bystander killing of receptor-negative cells in mixed populations containing as few as 10% phOx-receptor-positive cells. Functional phOx scFv receptors were stably expressed on B16-F1 melanoma tumors in vivo. Treatment of mice bearing established phOx-receptor-positive tumors with phOx-beta G-PEG and HAMG significantly (P< or =.0005) suppressed tumor growth as compared with treatment with beta G-PEG and HAMG or prodrug alone. phOx was unstable in the serum, suggesting alternative haptens may be more suitable for in vivo applications. Our results show that therapeutic agents can be targeted to artificial hapten receptors in vitro and in vivo. The expression of artificial receptors on target cells may allow preferential delivery of therapeutic or imaging molecules to sites of transgene expression.
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PMID:Hapten-directed targeting to single-chain antibody receptors. 1504 63

Combination therapy can help overcome limitations in the treatment of heterogeneous tumors. In the current study, we examined whether multiple therapeutic agents could be targeted to anti-dansyl single-chain antibodies (DNS scFv) that were anchored on the plasma membrane of cancer cells. Functional DNS scFv could be stably expressed on CT-26 colon cancer cells both in vitro and in vivo. Dansyl moieties were covalently attached to recombinant beta-glucuronidase (betaG) and interleukin 2 (IL-2) via a flexible poly(ethylene glycol) linker to form DNS-PEG-betaG and DNS-PEG-IL-2 conjugates. The conjugates displayed enzymatic and splenocyte-stimulatory activities, respectively, that were similar to those of the unmodified proteins. The conjugates selectively bound CT-26 cells that expressed anti-DNS scFv (CT-26/DNS cells) but not CT-26 cells that expressed control scFv (CT-26/phOx cells). DNS-PEG-betaG preferentially activated a glucuronide prodrug (BHAMG) of p-hydroxy aniline mustard at CT-26/DNS cells in culture and accumulated in subcutaneous CT-26/DNS tumors after intravenous administration. Systemic administration of DNS-PEG-IL-2 or DNS-PEG-betaG and BHAMG significantly delayed the growth of CT-26/DNS but not control CT-26/phOx tumors. Combination treatment with DNS-PEG-betaG and BHAMG followed by DNS-PEG-IL-2 therapy significantly suppressed the growth of CT-26/DNS tumors as compared to either single-agent regimen. These results show that at least two DNS-modified therapeutic agents can be selectively delivered to DNS scFv receptors in vitro and in vivo, allowing combination therapy of DNS scFv-modified tumors.
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PMID:Combination cancer therapy by hapten-targeted prodrug-activating enzymes and cytokines. 1670 8

Gene-mediated enzyme prodrug therapy (GDEPT) seeks to increase the therapeutic index of anti-neoplastic agents by promoting selective activation of relatively nontoxic drug derivatives at sites of specific enzyme expression. Glucuronide prodrugs are attractive for GDEPT due to their low toxicity, bystander effect in the interstitial tumor space and the large range of possible glucuronide drug targets. In this study, we expressed human, murine and Esherichia coli beta-glucuronidase on tumor cells and examined their in vitro and in vivo efficacy for the activation of glucuronide prodrugs of 9-aminocamptothecin and p-hydroxy aniline mustard. We show that (1) fusion of beta-glucuronidase to the Ig-like C(2)-type and Ig-hinge-like domains of the B7-1 antigen followed by the B7-1 transmembrane domain anchored high levels of active murine and human beta-glucuronidase on cells, (2) strong bystander killing of tumor cells was achieved in vitro by murine beta-glucuronidase activation of prodrug, (3) potent in vivo anti-tumor activity was achieved by prodrug treatment of tumors that expressed murine beta-glucuronidase and (4) the p-hydroxy aniline prodrug was more effective in vivo than the 9-aminocamptothecin prodrug. Our results demonstrate that surface expression of murine beta-glucuronidase for activation of a glucuronide prodrug of p-hydroxy aniline mustard may be useful for more selective therapy of cancer.
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PMID:Membrane-localized activation of glucuronide prodrugs by beta-glucuronidase enzymes. 1697 28


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