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)

In an attempt to better understand breast tumors sensitivity or resistance to anticancer drugs, the main drug-metabolizing enzyme systems were evaluated in both breast tumors and their corresponding peritumoral tissues in 12 patients. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); glutathione S-transferases (GST-alpha, -mu, and -pi); and epoxide hydrolase. The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: GST; total glutathione; UDP-glucuronosyltransferase; beta-glucuronidase; sulfotransferase; and sulfatase. Results showed the absence of all probed cytochromes P-450 in both tumoral and peritumoral tissues. GST activity was significantly (P < 0.05) higher in tumors (mean +/- SD, 399 +/- 362 nmol/min/mg) than in corresponding peritumoral tissues (86 +/- 67). The GST isoenzymes GST-mu and GST-pi (determined by immunoblotting) were also higher in tumors than in corresponding peritumoral tissues (3- and 5-fold, respectively). Both GST-mu and GST-pi levels were significantly correlated with GST activity. GST-alpha was not detected in either tumoral or peritumoral tissues. Glutathione levels in tumors (22 +/- 23 nmol/mg protein) were not statistically different from peritumoral tissues (11 +/- 12). Epoxide hydrolase was expressed at similar levels in tumors and peritumoral tissues. The glucuronide-forming enzyme UDP-glucuronosyltransferase was 5-fold lower in tumors (0.1 +/- 0.2 nmol/h/mg) than in peritumoral tissues (0.5 +/- 1), whereas the opposite was observed for the hydrolytic enzyme beta-glucuronidase, which was 6-fold higher in tumors (736 +/- 1392 nmol/h/mg) compared to peritumoral tissues (125 +/- 75). No difference was noted between tumoral and peritumoral tissues for sulfotransferase (1 +/- 2 nmol/h/mg), but the corresponding hydrolytic enzyme (sulfatase) was 2-fold higher in tumoral tissues (14 +/- 15 nmol/h/mg) than in peritumoral tissues (6 +/- 2). In conclusion, several differences were observed between human breast tumors and peritumoral tissues for many conjugating enzymes (GST-mu, GST-pi, and UDP-glucuronosyltransferase) and hydrolytic enzymes (sulfatase and beta-glucuronidase). These noteworthy differences between tumoral and peritumoral tissues with regard to their main drug-metabolizing enzymes could play a role in the relative drug sensitivity or insensitivity of human breast cancer tissues to chemotherapeutic agents and could be potential targets for chemotherapeutic interventions.
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PMID:Main drug-metabolizing enzyme systems in human breast tumors and peritumoral tissues. 833 60

To elucidate the effects of the intestinal microflora on absorption and activation of glutathione conjugates of 4,5-epoxy-4,5-dihydro-1-nitropyrene (1-NP 4,5-oxide) and 9,10-epoxy-9,10-dihydro-1-nitropyrene (1-NP 9,10-oxide), we investigated the biological activities of the microflora in specific-pathogen-free (SPF) mice and SPF mice treated with various antibiotics and established the methodology of antibiotic treatment to eliminate the intestinal microflora. Mice were given various kinds of antibiotics by intragastric gavage twice a day for five days. A mixture of antibiotics bacitracin (BC), neomycin (NM) and streptomycin (SM) was the most effective in reducing the various activities of the intestinal microflora. The treatment decreased the bacterial counts and the activities of enzymes of the intestinal contents cysteine conjugate beta-lyase (beta-lyase), beta-glucuronidase and nitroreductase which were derived from the intestinal microflora, but did not affect the activities of gamma-glutamyltransferase and aminopeptidase which were derived from host tissue cells. Furthermore, the treatment did not affect absorption of glucose from the intestinal tract, body weight or liver enzyme activities. The treatment with only an aminoglycoside antibiotic, kanamycin or NM, decreased neither the number of anaerobes in the intestine nor the beta-lyase or nitroreductase activities from the intestinal contents. Glutathione conjugates of [3H]-1-NP oxides were administered to two groups of ICR mice that had been treated with antibiotics (BC, NM, SM) or saline (control group) orally. The radioactivity in the blood increased and reached the maximum level 2 or 3 h after administration of the conjugates in the control group; however, that in the antibiotic-treated group was only slightly increased if at all. Excretion of [3H]-labeled metabolites into the urine was approximately 20% of the total dose in the control group, but it was < 2% in the antibiotic-treated group during 48 h. After 48 h, DNA in the lower intestinal mucosa was extracted and the DNA adducts were analyzed by the 32P-postlabeling method. Three new DNA adducts were detected in the lower intestinal mucosa of the control group but not of the antibiotic-treated group. These results suggest that the intestinal microflora plays an important role in absorption of the metabolites of glutathione conjugates of 1-NP oxides from the intestinal tract and activation of the metabolites in the intestine.
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PMID:Biological activities of the intestinal microflora in mice treated with antibiotics or untreated and the effects of the microflora on absorption and metabolic activation of orally administered glutathione conjugates of K-region epoxides of 1-nitropyrene. 850 79

To investigate the uptake and long-distance translocation of sulphate in plants, we have characterized three cell-type-specific sulphate transporters, Sultr1;1, Sultr2;1 and Sultr2;2 in Arabidopsis thaliana. Heterologous expression in the yeast sulphate transporter mutant indicated that Sultr1;1 encodes a high-affinity sulphate transporter (Km for sulphate 3.6 +/- 0.6 microM), whereas Sultr2;1 and Sultr2;2 encode low-affinity sulphate transporters (Km for sulphate 0.41 +/- 0.07 mM and >/= 1.2 mM, respectively). In Arabidopsis plants expressing the fusion gene construct of the Sultr1;1 promoter and green fluorescent protein (GFP), GFP was localized in the lateral root cap, root hairs, epidermis and cortex of roots. beta-glucuronidase (GUS) expressed with the Sultr2;1 promoter was specifically accumulated in the xylem parenchyma cells of roots and leaves, and in the root pericycles and leaf phloem. Expression of the Sultr2;2 promoter-GFP fusion gene showed specific localization of GFP in the root phloem and leaf vascular bundle sheath cells. Plants continuously grown with low sulphate concentrations accumulated high levels of Sultr1;1 and Sultr2;1 mRNA in roots and Sultr2;2 mRNA in leaves. The abundance of Sultr1;1 and Sultr2;1 mRNA was increased remarkably in roots by short-term stress caused by withdrawal of sulphate. Addition of selenate in the sulphate-sufficient medium increased the sulphate uptake capacity, tissue sulphate content and the abundance of Sultr1;1 and Sultr2;1 mRNA in roots. Concomitant decrease of the tissue thiol content after selenate treatment was consistent with the suggested role of glutathione (GSH) as a repressive effector for the expression of sulphate transporter genes.
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PMID:The roles of three functional sulphate transporters involved in uptake and translocation of sulphate in Arabidopsis thaliana. 1092 11

Formation of depurinating adducts by reaction of catechol estrogen-3,4-quinones with DNA was proposed to be a tumor initiating event by estrogens [E.L. Cavalieri et al. (1997) Proc. Natl Acad. Sci. USA, 94, 10937-10942]. Under estrogenic imbalance, oxidation of catechol estrogens to quinones may compete with their detoxification by protective enzymes. The quinones formed can be detoxified by reaction with glutathione (GSH) or can covalently bind to DNA. To provide more support for this hypothesis, we developed a method to identify and quantify GSH, cysteine (Cys) and N-acetylCys conjugates of 4-hydroxyestrogens (4-OHE) in the kidneys of male Syrian hamsters treated with 4-hydroxyestradiol (4-OHE2) by intraperitoneal injection. The highest level of conjugates was observed 1 h after treatment, and almost none was detected after 24 h. Dose-response studies indicated conjugate formation after treatment with 0.5 micromol of 4-OHE2/100 g body weight, and formation increased up to a treatment level of 12 micromol/100 g body weight. GSH, Cys and N-acetylCys conjugates of 4-OHE were identified in the picomole range by high-performance liquid chromatography (HPLC) with multichannel electrochemical detection and confirmed by HPLC/tandem mass spectrometry. Treatment of tissue homogenates with beta-glucuronidase/sulfatase at 37 degrees C for 6 h before extraction resulted in a 12- to 20-fold increase in Cys conjugates from picomole to nanomole levels. Similar enhancement was observed by just incubating the tissue at 37 degrees C for 6 h. Evidence for the 4-OHE-1-N7Gua depurinating adducts was obtained by mass spectrometry. We conclude that GSH and Cys conjugates of the 4-OHE and the 4-OHE-N7Gua adducts can be utilized as biomarkers to detect estrogenic imbalance and potential susceptibility to tumor initiation.
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PMID:Catechol estrogen conjugates and DNA adducts in the kidney of male Syrian golden hamsters treated with 4-hydroxyestradiol: potential biomarkers for estrogen-initiated cancer. 1123 91

The in vitro and in vivo disposition of DPC 423 was investigated in mice, rats, dogs and humans and the metabolites characterized by LC/MS, LC/NMR and high field-NMR. The rodents produced several metabolites that included an aldehyde (M1), a carboxylic acid (M2), a benzyl alcohol (M3), glutamate conjugates (M4 and M5), an acyl glucuronide (M6) and its isomers; a carbamyl glucuronide (M7); a phenol (M8) and its glucuronide conjugate (M9), two glutathione adducts (M10 and M11), a sulfamate conjugate (M12), isomers of an oxime metabolite (M13), and an amide (M14). Humans and dogs produced less complex metabolite profiles than rats. While unchanged DPC 423 was the major component in plasma and urine samples, differences in the metabolic disposition of this compound among species were noted. M1 is believed to be rapidly oxidized to the carboxylic acid (M2), which forms the potentially reactive acyl glucuronide (M6). The formation of novel glutamate conjugates (M4 and M5) and their role in depleting endogenous glutathione have been described previously. The carbamyl glucuronide M7, found as the major metabolite in rats and in other species, was considered nonreactive and was easily hydrolyzed to the parent compound in the presence of beta-glucuronidase. The identification of GSH adducts M10 and M11 led us to postulate the existence of at least two reactive intermediates responsible for their formation, an epoxide and possibly a nitrile oxide, respectively. Although the formation of GSH adducts such as M10 from epoxides has been described before, there are no reports to date describing the existence of a GSH adduct (M11) of an oxime. The formation of a sulfamate conjugate (M12) formed by direct coupling of sulfate to the nitrogen of benzylamine is described. A mechanism is proposed for the formation of the oxime (M13) that involves sequential oxidation of the benzylamine to the corresponding hydroxylamine and nitroso intermediate. The rearrangement of the nitroso intermediate is believed to produce the oxime (M13). In vitro studies suggested that both the oxime (M13) and the aldehyde (M1) were precursors to the carboxylic acid (M2). This is the first demonstration of carboxylic acid formation via an oxime intermediate produced from an amine. The stability of DPC423 in plasma obtained from several species was studied. Significant species differences in the plasma stability of DPC 423 were observed. The formation of the aldehyde metabolite (M1) was found to be catalyzed by a semicarbazide-sensitive monoamine oxidase (SSAO) found in plasma of rabbits, dogs, and rhesus monkeys. Rat, chimpanzee, and human plasma did not form M1.
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PMID:Disposition of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'- (methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (DPC 423) by novel metabolic pathways. Characterization of unusual metabolites by liquid chromatography/mass spectrometry and NMR. 1180 May 97

The mechanisms controlling plant resistance to necrotrophic fungal pathogens are poorly understood. We previously reported on Ep5C, a gene shown to be induced by the H(2)O(2) generated during a plant-pathogen interaction. To identify novel plant components operating in pathogen-induced signaling cascades, we initiated a large-scale screen using Arabidopsis thaliana plants carrying the beta-glucuronidase reporter gene under control of the H(2)O(2)-responsive Ep5C promoter. Here, we report the identification and characterization of a mutant, ocp3 (for overexpressor of cationic peroxidase 3), in which the reporter construct is constitutively expressed. Healthy ocp3 plants show increased accumulation of H(2)O(2) and express constitutively the Glutathione S-transferase1 and Plant Defensine 1.2 marker genes, but not the salicylic acid (SA)-dependent pathogenesis-related PR-1 gene. Strikingly, the ocp3 mutant shows enhanced resistance to the necrotrophic pathogens Botrytis cinerea and Plectosphaerella cucumerina. Conversely, resistance to virulent forms of the biotrophic oomycete Hyaloperonospora parasitica and the bacterial pathogen Pseudomonas syringae pv tomato DC3000 remains unaffected in ocp3 plants when compared with wild-type plants. Consistently with this, ocp3 plants are not affected in SA perception and express normal levels of PR genes after pathogen attack. To analyze signal transduction pathways where ocp3 operates, epistasis analyses between ocp3 and pad4, nahG, npr1, ein2, jin1, or coi1 were performed. These studies revealed that the resistance signaling to necrotrophic infection in ocp3 is fully dependent on appropriate perception of jasmonic acid through COI1 and does not require SA or ethylene perception through NPR1 or EIN2, respectively. The OCP3 gene encodes a homeodomain transcription factor that is constitutively expressed in healthy plants but repressed in response to infection by necrotrophic fungi. Together, these results suggest that OCP3 is an important factor for the COI1-dependent resistance of plants to infection by necrotrophic pathogens.
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PMID:An Arabidopsis homeodomain transcription factor, OVEREXPRESSOR OF CATIONIC PEROXIDASE 3, mediates resistance to infection by necrotrophic pathogens. 1592 48

Glutathione S-transferases (GSTs) are regulated by various stimuli at the transcriptional level. In this study, a 2,640-bp promoter sequence of a mustard GST gene, BjGSTF2, was cloned. Several truncated BjGSTF2 promoters were generated by 5'-deletion, fused to the beta-glucuronidase (GUS) coding sequence and the chimeric genes expressed in Arabidopsis thaliana. Transgene expression in GST2623::GUS plants carrying the longest promoter varied considerably. GUS activity was high in the roots, cotyledons, anthers and both ends of the silique, but it was low or barely detectable in the leaves, seeds, petals and stamens. Analysis of transgenic plants expressing the GUS gene under the control of different truncated BjGSTF2 promoters revealed several regions that possessed cis-acting elements required for the basal and induced expression by H(2)O(2), salicylic acid and 1-aminocyclopropane-1-carboxylate and down-regulation by spermidine. The results also showed that the GUS activity of GST2623::GUS coincided well with the H(2)O(2) accumulation pattern in cultured leaf-disc explants during the regeneration process.
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PMID:Molecular characterization of a Phi-class mustard (Brassica juncea) glutathione S-transferase gene in Arabidopsis thaliana by 5'-deletion analysis of its promoter. 1592 64

The effect of reduced glutathione (GSH) was studied on exocytosis triggered by 4-hydroxynonenal in HL-60 cells induced to differentiate towards the granulocytic cell line by dimethylsulfoxide; we measured beta-glucuronidase secretion from cells incubated at 37 degrees C in the presence of 5 mM GSH. GSH addition to the cell suspensions failed to induce any significant change of the exocytosis stimulated by HNE concentrations between 10(-8) and 10(-6) M. In contrast however, 5 mM GSH was able to fully prevent the release of lactate dehydrogenase observed in the presence of 50 microM HNE, a concentration much higher than that able to stimulate the exocytotic secretion. As the activation of phosphoinositide-specific phospholipase C (PLC) has been shown to play a major role in HNE-induced exocytosis, we studied the GSH effect on the breakdown of phosphatidylinositol-4,5-bisphosphate added to plasma membranes isolated from rat neutrophils and incubated in the presence of increasing concentrations of the aldehyde. In neutrophil membranes HNE induced a significant increase of PLC activity when used in the same concentrations as those able to stimulate beta-glucuronidase secretion in DMSO-differentiated HL-60 cells; the presence of 5 mM GSH failed to prevent its action. Our results suggest that these low aldehyde concentrations, which have actually been found in exudates, may increase tissue damage in inflammation through the release of lytic enzymes by neutrophils; it seems unlikely that their effects could be influenced by the levels of -SH groups present in the exudate and by its protein concentration.
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PMID:The exocytosis induced in HL-60 cells by 4-hydroxynonenal, a lipid peroxidation product, is not prevented by reduced glutathione. 1618 24

Dietary glutamine has been suggested to preserve structural and functional integrity of the gut and high dose bolus glutamine has been hypothesized to protect against potentially fatal endotoxic shock, hyperthermic stress, and side effects of chemotherapy. In this study, we aimed to relate the ability of high dose oral bolus glutamine to mitigate the severe diarrhea induced by 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) chemotherapy to specific cytoprotective mechanisms [heat shock response, glutathione (GSH)] in gut and tumor tissues. Female rats bearing Ward colon tumor received CPT-11 (125 mg x kg(-1) x d(-1)x 3 d) with or without an oral glutamine bolus (0.75 g/kg) administered 30 min prior to each CPT-11 dose. Glutamine reduced incidence and severity of late-onset diarrhea following CPT-11 treatment (P < 0.05) and was associated with potentially beneficial and protective responses in the colon: 1) a 3.1- to 7.2-fold increase of heat shock protein (Hsp)25,-70, and -90alpha (P < 0.05); 2) increased reduced GSH (rGSH):oxidized GSH ratio (P < 0.05); 3) prevention of upregulated activity of a key bacterial enzyme (beta-glucuronidase) in the cecal content that mediates CPT-11 intestinal toxicity (P < 0.05); and 4) increased proportions of CD3+CD8+ lymphocytes and memory CD8+ subset in mesenteric lymph nodes following CPT-11 therapy. By contrast, glutamine treatment did not alter CPT-11's antitumor activity, the amino acid concentrations, Hsp expression, or the ratio of rGSH:oxidized GSH in the tumor. Our data demonstrate a striking dichotomy in the response of tumor and host to oral glutamine administration, concurring with the concept that this nutrient may favorably alter the balance between the host and tumor.
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PMID:Bolus oral glutamine protects rats against CPT-11-induced diarrhea and differentially activates cytoprotective mechanisms in host intestine but not tumor. 1835 29

Tire particles (TP) represent a significant component of urban air pollution (PM), constituting more than 10% of PM10 mass at urban locations with heavy traffic. The purpose of this study was to evaluate the effects of size-fractionated TP in an animal exposure model frequently used to assess the health effects of air pollutants. Potential pro-inflammatory and toxic effects of TP2.5 (<2.5 microm) and TP10 (<10 microm) were investigated through instillation of suspensions of these materials in BALB/c mice. Bronchoalveolar lavage fluid (BALF) was screened for total protein, lactate dehydrogenase (LDH), alkaline phosphatase (AP), and beta-glucuronidase (B-Gluc) as markers of cytotoxicity; glutathione (GSH) and superoxide dismutase (SOD) as markers of oxidative potential; and tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), and inflammatory cells as markers of inflammation. Concomitantly, histological analysis of TP-exposed lungs was performed. A single intratracheal instillation of 10 microg/100 microl, 100 microg/100 microl or 200 microg/100 microl was performed, and after 24h mice were euthanized and BALF examined. Inflammatory cellular profiles showed dose-dependent responses after TP10 exposure, while strong cytotoxic effects, including increases in total protein, LDH and AP, were observed to be associated to TP2.5 exposure. Histologically, TP10-treated lungs mainly showed inflammatory tissue infiltration, in contrast to TP2.5-treated lungs, where lysis of the alveolar barrier appeared to be the most characteristic lesion. Our biochemical, cytological, and histological results indicated differential lung toxicity mechanisms elicited by size-fractionated TP, in agreement with other studies performed in in vivo systems that have shown that lung responses to inhaled or instilled particles are affected by particle size. We conclude that lung toxicity induced by TP10 was primarily due to macrophage-mediated inflammatory events, while toxicity induced by TP2.5 appeared to be related more closely to cytotoxicity.
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PMID:Lung toxicity induced by intratracheal instillation of size-fractionated tire particles. 1950 37


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