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)

Auranofin, an oral chrysotherapeutic agent effective in the treatment of rheumatoid arthritis (RA), was found to be a potent, noncytotoxic inhibitor of IgG-RF immune complex-induced lysosomal enzyme release (LER) from human leukocytes. At a concentration of 1 microg Au/ml (5 microM), auranofin produced a marked reduction in beta-glucuronidase (100%), acid phosphatase (88%), and lysozyme (72%) release. In contrast, gold sodium thiosulfate (GST, an injectable gold compound) had no inhibitory activity on LER at equivalent gold concentrations (i.e., 1 microg Au/ml) and only modest activity (less than 36% inhibition) at concentrations as high as 40 microg Au/ml. The 50% inhibitory dose (LD50) of auranofin on LER was calculated to be 3-4 microM (0.6-0.8 microg Au/ml). Blood gold levels in auranofin-treated RA patients were found to be within the range required for in vitro inhibition of LER, and correlated with decreases in IgG, RF titers, and IgG-RF immune-complex formation in vitro. These results suggest that the therapeutic action of auranofin may be caused, at least in part, by inhibition of LER and/or decreases in immune-complex formation.
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PMID:Effect of auranofin, a new antiarthritic agent, on immune complex-induced release of lysosomal enzymes from human leukocytes. 10 28

Since human colorectal tumors are insensitive to most chemotherapeutic agents, there is a need for the discovery of new drugs that would show activity against this disease. In an attempt to better appreciate the relevance of a widely used mouse colon tumor (colon adenocarcinoma Co38) as a screening model for human colorectal tumors, we compared the main phase I and phase II drug-metabolizing enzyme systems in both tumoral and nontumoral colon tissues. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C, 2E1, and 3A), epoxide hydrolase, and glutathione-S-transferases (GST-alpha, -mu, and -pi). The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: total cytochrome P-450, 1-chloro-2,4-dinitrobenzene-GST, selenium-independent glutathione peroxidase, 3,4-dichloronitrobenzene-GST, ethacrynic acid-GST, total glutathione, epoxide hydrolase, UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, and sulfatase. Results obtained by Western blot showed that mouse colon adenocarcinoma Co38 did not express any of the probed cytochromes P-450, whereas human colorectal tumors expressed only low levels of cytochrome P-450 3A. GST-alpha and GST-pi were detected in all tumoral and nontumoral tissues of both species. The neutral GST-mu was expressed in all murine tissues investigated and was found to be polymorphic in human tissues. For human peritumoral and tumoral colorectal tissues there was no significant difference between GST isoenzyme levels, whereas mouse colon adenocarcinoma Co38 had a lower expression of GST-mu and GST-pi, compared to normal mouse colon. Enzymatic activities for glutathione peroxidase, 3,4-dichloronitrobenzene-GST, and ethacrynic acid-GST confirmed the Western blot results for GST-alpha, GST-mu, and GST-pi, respectively. Total GSH levels were similar between murine and human tumors but were 3-fold higher in human tumors than in peritumoral tissues, whereas they were 7-fold lower in mouse colon tumor Co38, compared to normal mouse colon. Epoxide hydrolase was not expressed in either mouse colon adenocarcinoma Co38 or normal mouse colon tissues, whereas it was expressed in human colon peritumoral and tumoral tissues at similar levels. No significant difference was observed between human tumors and peritumoral tissues for UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, and sulfatase. For murine colon tissues, the conjugation pathways (UDP-glucuronosyltransferase and sulfotransferase) were lower in colon adenocarcinoma Co38, whereas the converse was observed for the corresponding hydrolytic enzymes (beta-glucuronidase and sulfatase).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Comparison of mouse and human colon tumors with regard to phase I and phase II drug-metabolizing enzyme systems. 142 2

We have previously shown that 2-hydroxamino-1-methyl-6-phenylimidazo[4,5-b]pyridine(2-h ydroxamino-PhIP) is the principal metabolite leading to mutations in Salmonella typhimurium TA98 and DNA damage in mammalian cells. In rat hepatocytes this metabolite can be further conjugated to 2-(N-beta-D-glucuronopyranosyl (hydroxamino)-1-methyl-6-phenylimidazo[4, 5-b]pyridine[N(OH)-gluc-PhIP]. Its rate of formation was increased in hepatocytes from polychlorinated biphenyl (PCB)-pretreated animals. This metabolite is the main metabolite of PhIP in bile and it is hydrolyzed both by human and rat intestinal bacteria. Smaller amounts are excreted into urine. The evidence for the proposed structure is based on 1H- and 13C-NMR, beta-glucuronidase-lability giving 2-hydroxamino-PhIP upon hydrolysis and on the results obtained by using biochemical enzyme inhibitors. N(OH)-gluc-PhIP may be important for genotoxic lesions and tumors of 2-amino-1methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) in extrahepatic tissue. In hepatocytes and bile from PCB-pretreated rats a PhIP-glutathione conjugate, 2-glutathionyl-1-methyl-6-phenylimidazo[4,5-b]pyridine (GSH-PhIP) was also found. The evidence for the proposed structure is based on 1H-NMR and high-resolution mass spectrometry. The metabolite can also be produced by a direct nucleophilic substitution of the nitro group in 2-nitro-PhIP by glutathione (GSH) in vitro. The metabolite did not form from 2-hydroxamino-PhIP and GSH either directly or in the presence of glutathione S-transferase. The formation of GSH-PhIP in rat liver and isolated cells only at a high rate of 2-hydroxamino-PhIP formation (PCB-treated animals) indicates that 2-nitro-PhIP may be formed in the liver during such N-oxidation of PhIP.
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PMID:Formation of a glutathione conjugate and a semistable transportable glucuronide conjugate of N2-oxidized species of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rat liver. 174 23

The influence of high fat or food-restricted diets on key enzymes associated with polycyclic aromatic hydrocarbon metabolism was assessed in liver, lung, kidney and stomach of rats. Animals had access ad libitum to the AIN-76A purified diet (control) or were given 65% of the intake of controls for 3 wk. The high fat diet was isoenergetic to the control diet by substituting corn oil for equal energy from carbohydrate and addition of cellulose to obtain equal energy density. Activities of arylhydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase were significantly increased in lungs of food-restricted rats and decreased by the high fat diet but were not altered in liver. Both diets increased arylhydrocarbon hydroxylase approximately twofold in kidney. Glucose 6-phosphate and 6-phosphogluconate dehydrogenase were lowered in lung, kidney and liver by the high fat diet. Hepatic glutathione S-transferase was increased by high fat feeding. Food restriction decreased activities of arylsulfatase and beta-glucuronidase about 40% in lung. Hepatic arylsulfatase was also decreased about 40% by this treatment. Changes in hydrolase activities in livers and lungs of animals maintained on restricted diets raises in the interesting possibility that net production of glucuronide and sulfate conjugates of carcinogens by the liver and their hydrolysis in lung is altered by food restriction.
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PMID:Enzyme activities associated with carcinogen metabolism in liver and nonhepatic tissues of rats maintained on high fat and food-restricted diets. 189 48

Significant increases in activities of epoxide hydrolase, UDP-glucuronosyltransferase, and glutathione S-transferase, and marked reductions in cytochrome P-450 mixed-function oxidase systems occur in hyperplastic nodules induced in rat liver by chemical mutagens. In contrast, activities of both oxidative (Phase I) and conjugative (Phase II) enzymes are decreased in hepatocellular carcinomas induced by peroxisome proliferators. The present work compares alterations induced by chemical mutagens or peroxisome proliferators with changes in enzyme activities that occur in primary and secondary hepatic tumors in man. The above activities, along with beta-glucuronidase and arylsulfatase, were measured in liver samples from 6 normal livers obtained at immediate autopsy, and liver specimens obtained by surgical biopsy from the following patients: 8 with hepatomas, 5 with nonmetastatic colorectal carcinomas, and 14 with metastatic colorectal carcinomas. Cytochromes P-450MP and P-450NF in addition to epoxide hydrolase were measured by immunoquantitation. Enzymes involved in conjugation reactions were either assayed fluorometrically (UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, and sulfatase) or spectrophotometrically (glutathione S-transferase) using umbelliferyl substrates or 1-chloro-2,4-dinitrobenzene. Secondary hepatic tumors showed no significant change in drug-metabolizing enzymes, in contrast to primary hepatomas, which displayed decreases in all of the measured drug metabolizing enzymes. Arylsulfatase was markedly depressed in primary hepatomas (14% of normal values). Thus, activities of drug-metabolizing enzymes in human primary tumors resemble those associated with altered hepatic foci induced by peroxisome proliferators such as ciprofibrate. The marked decreases in sulfatase that occurred in primary but not in secondary human tumors suggest that sulfation of endogenous compounds and xenobiotics may differ in patients with primary and secondary hepatic tumors.
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PMID:Hepatic drug-metabolizing enzymes in primary and secondary tumors of human liver. 302 21

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

Using male Fischer 344 rats classified as young (2-4 months), middle aged (12-14 months), and old (22-25 months), the activities of several Phase I and Phase II biotransformation pathways in the large intestine were investigated, including benzo[a]pyrene hydroxylase (BPOH), alcohol dehydrogenase (ADH), glutathione S-transferase (GST), glutathione peroxidase (GSH-PX), beta-glucuronidase (BG), and microsomal and nuclear glucuronyltransferase (UDPGT). Levels of oxidized (GSSG) and reduced (GSH) glutathione and uridine 5'-diphosphoglucuronic acid (UDPGA) were also measured. BPOH increased 33% in old rats, while ADH and BG activity remained unchanged with age. Nuclear UDPGT remained unchanged with age, whereas form I of GSH-PX declined slightly in old rats. GST, microsomal UDPGT, and form II of GSH-PX declined by 38, 37 and 44%, respectively, in old rats. The decrease in GST and microsomal UDPGT was also significant in middle aged rats. Levels of colonic GSH, GSSG and UDPGA were found to be unchanged with age. These in vitro data suggest the possibility that if reactive intermediates are generated to the same extent in old rats as in young rats, decreased detoxification mechanisms in the old rat may increase susceptibility of the colon to actions of chemical carcinogens.
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PMID:Changes in phase I and phase II biotransformation with age in male Fischer 344 rat colon: relationship to colon carcinogenesis. 311 59

The capacity of animal models to predict the responses of humans to carcinogenic agents in light of the occurrence of human heterogeneity is assessed in this paper. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. At the same time, it is believed that the conventional rodent models, which are usually highly inbred and reared in standard ways, display a very homogeneous response to toxic agents, including carcinogens. The question then becomes, To which narrow band of the broad spectrum of human responses can specific animal models likely be extrapolated? First, the occurrence of human heterogeneity is examined with respect to a broad range of biological characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, glutathione S-transferase activity, beta-glucuronidase activity, debrisoquine hydroxylation, and DNA adduct formation), with particular emphasis on those which affect responses to carcinogens. Second, the occurrence of heterogeneity for selected animal models for these characteristics is assessed and the outcomes are related to the spectrum of human responses noted above.
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PMID:Animal extrapolation and the challenge of human heterogeneity. 382 97

The anti-inflammatory effects of gold compounds include suppression of PMN lysosomal enzyme release. Since lysosomal products can provoke PMN aggregation, we assessed the effect of two gold compounds, auranofin and GST, on suppressing aggregation, degranulation, and metabolic functions of the cells. Aggregation of 1 x 10(7) cytochalasin B-treated PMNs in response to 2 x 10(-7)M FMLP, as assessed by light scattering, was inhibited in a dose-dependent fashion by both drugs. Concentrations of auranofin ranging from 5 to 20 microM caused 30.8% to 89% inhibition, whereas 200 microM GST reduced aggregation by only 32%. FCS or BSA added to suspensions of normal PMNs considerably reduced the gold compound inhibitory effect on PMN aggregation. Cell viability assessed by dye exclusion and lactate dehydrogenase release was unaffected by the drugs. The suppressive activities of the drugs could not be removed by washing the PMNs. Correspondingly, the drugs suppressed lysosomal enzyme release induced by FMLP of PMNs rendered secretory with cytochalasin B. Concentrations of 20 microM auranofin and 200 microM GST resulted, respectively, in a 61.5% and 19.3% reduction of release of lysozyme, 61.7% and 27.1% reduction of beta-glucuronidase, 84.8% and 33.7%s reduction of myeloperoxidase, and 50.0% and 25.0% reduction of lactoferrin. Furthermore, auranofin inhibited 14C-1-glucose oxidation through the hexose monophosphate shunt in response to stimulation by either PMA or methylene blue. The in vivo studies suggested that auranofin could prevent neither neutropenia induced by zymosan-activated serum nor a corresponding rise in plasma lactoferrin levels. These findings suggest that the beneficial effect of gold compounds in rheumatoid arthritis are unlikely to be related to their ability to dampen PMN activation in vivo.
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PMID:Correlation of in vitro and in vivo effects of gold compounds on leukocyte function: possible mechanisms of action. 628 1

Transcriptional activation of the soybean (Glycine max) GH2/4 gene (also referred to as Gmhsp26-A) and increase in abundance of the GH2/4 mRNA (also referred to as pCE54) have been previously shown to occur following treatment of soybean seedlings with auxins, nonauxin analogs, heavy metals, and a variety of other agents. To determine whether the GH2/4 promoter is responsive to an array of different agents, we have analyzed the inducibility of the GH2/4 promoter fused to the beta-glucuronidase reporter gene in transgenic tobacco (Nicotiana tabacum) plants. We have shown that a wide variety of chemical agents induce this promoter in a tissue-specific and concentration-dependent manner. In addition, we have used an affinity-purified antibody raised against recombinant GH2/4 protein to show that the GH2/4 protein increases in response to auxin application and is localized in the cytosol of soybean cells. Recombinant GH2/4 protein can be purified to homogeneity on a glutathione-agarose resin, and the purified protein has glutathione S-transferase activity when assayed with the substrate 1-chloro-2,4-dinitrobenzene.
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PMID:The soybean GH2/4 gene that encodes a glutathione S-transferase has a promoter that is activated by a wide range of chemical agents. 763 Sep 72


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