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)

Hepatic enzymes connected with the formation and metabolism of free D-glucuronic acid were affected in rats after treatment with disulfiram or diethyldithiocarbamate (300 mg/kg, intragastrically, per day, 4 X). The activities of UDPglucose dehydrogenase, UDPglucuronic acid pyrophosphatase, UDPglucuronosyltransferase and L-gulonate dehydrogenase were enhanced, while those of glucose-6-phosphate dehydrogenase, beta-glucuronidase and D-glucuronolactone dehydrogenase were inhibited. These changes were more pronounced with disulfiram than diethyldithiocarbamate. Treatment with phenobarbital (80 mg/kg, i.p., per day, 4 X) enhanced UDP glucuronosyl-transferase, but brought about different effects on the other enzymes. Concurrent administration of phenobarbital with disulfiram or diethyldithiocarbamate led to potentiation or antagonism of the primary effects of each compound when given alone. The results suggest that activation of the D-glucuronic acid pathway may proceed in various ways, and that it is not necessarily followed by a simultaneous induction of the microsomal mixed-function oxygenase activity.
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PMID:Modifications of drug metabolism by disulfiram and diethyldithiocarbamate. II. D-Glucuronic acid pathway. 18 53

1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was administered to rats to study its effects on the enzyme activities of the D-glucuronic acid pathway in the liver, small intestine and kidney. 2. The UDP-glucuronosyl transferase activity of male albino rats given TCDD (80 mug/kg, one dose, i.p.) 6 days before killing was significantly increased in all tissues examined, and UDP-glucuronic acid pyrophosphatase activity was markedly decreased in the liver. D-Glucuronolactone and L-gulonate dehydrogenase activities in the liver and small intestine were slightly decreased after TCDD treatment. 3. The activities of UDP-glucose dehydrogenase and beta-glucuronidase were unchanged. 4. The 24 h urinary excretion of L-ascorbic acid was enhanced 8-fold, although no difference was detected in the excretion of D-glucaric acid between the control and experimental animals. 5. These results suggest an increased capacity for glucuronide conjugation after treatment with TCDD. 6. The lack of increase in the urinary excretion of D-glucaric acid further challenges its use as a reliable indicator of enhanced drug metabolism.
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PMID:Responses of the D-glucuronic acid pathway in rat tissues to treatment with tetrachlorodibenzodioxin. 68 88

The activities of certain drug metabolizing enzymes have been measured in liver and kidney slice preparations from domesticated birds. Aminopyrine demethylase activity was significantly lower in liver slices from the duck (Aylesbury X Pekin, Khaki-Campbell) than from the rat (Wistar), and in the Aylesbury X Pekin duck lower than in the turkey (Triple 6 FLX), chicken (Brown Leghorn, Rhode Island Red X Light Sussex) and goose (Emden X Doulouse). The microsomal cytochrome P-450 was lower in duck liver (Aylesbury X Pekin) than in rat liver, and the aniline hydroxylase and aminopyrine demethylase activities in a 10,000 g supernatant fraction of liver were lower in duck preparations (Aylesbury X Pekin, Khaki-Campbell) than rat preparations. These observations suggest that the duck is likely to be susceptible to drugs which are metabolized by the cytochrome P-450 containing mono-oxygenases. UDP-Glucuronyl transferase activity was not detectable in liver and kidney slices from two mature geese. This observation was not the outcome of a deficiency of UDP-glucuronic acid, rapid breakdown of glucuronide by beta-glucuronidase or the presence of a substance inhibitory to UDP-glucuronyl transferase. Liver slices from geese, ducks (Aylesbury X Pekin) and chickens contained low UDP-glucuronyl transferase and high sulphate conjugation enzyme activities, whereas the reverse was found in Khaki-Campbell ducks. The activities of UDP-glucuronyl transferase and the sulphate conjugation enzymes were both relatively high in liver slices from the turkey and rat. The kidney contained lower enzyme activities than the liver except in the duck (Aylesbury X Pekin), in which low activities of aminopyrine demethylase and UDP-glucuronyl transferase were present in slices of both organs. In liver slices from chickens and geese the activities of aminopyrine demethylase and the sulphate conjugation enzymes were similar in mature and immature birds, and the activity of UDP-glucuronyl transferase was considerably higher in chicks and goslings than in mature birds of the same species. In the chick the activities of aminopyrine demethylase, UDP-glucuronyl transferase and the sulphate conjugation enzymes were higher in the duodenum than the remainder of the alimentary tract. The activities of these enzymes in pieces of duodenum were as high as those in slices of liver. The inclusion of sulphate in the incubation medium produced a significant increase in the synthesis of p-nitrophenyl sulphate in liver slices and not kidney slices except those from the duck. The kidney slices seemed to produce sufficient sulphate for the reaction of the sulphate conjugation enzymes to proceed at the maximum rate, but the liver slices did not do so.
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PMID:Activities of mixed function oxidases, UDP-glucuronyl transferase and sulphate conjugation enzymes in galliformes and anseriformes. 81 57

The pluripotent human erythroleukaemia cell line, HEL, possesses erythrocytic, megakaryocytic and macrophage-like properties. With respect to signal transduction, HEL cells have been used as a model system for platelets, but little attention has been paid to their phagocytic properties. We studied the effects of various receptor agonists on the intracellular free Ca2+ concentration ([Ca2+]i) in HEL cells. Thrombin, platelet-activating factor (PAF), ATP, UTP, prostaglandins E1 and E2 (PGE1 and PGE2), the PGE2 analogue sulprostone and the stable PGI2 analogues iloprost and cicaprost increased [Ca2+]i. ADP was less effective than ATP, and UDP was unable to increase [Ca2+]i. The increases in [Ca2+]i induced by thrombin, PAF, ATP, UTP, iloprost and cicaprost were pertussis toxin-insensitive, whereas the increases induced by PGE2 and sulprostone were completely inhibited by the toxin. The increase in [Ca2+]i induced by PGE1 was partially inhibited by pertussis toxin. PGE2 did not desensitize the increase in [Ca2+]i induced by iloprost, and vice versa. PGE1 desensitized the response to PGE2 and iloprost but not vice versa. Adrenaline potentiated the iloprost- but not the PGE2-induced rise in [Ca2+]i. The phorbol ester phorbol 12-myristate 13-acetate completely blocked the rise in [Ca2+]i induced by ATP and PGE1, whereas the increases induced by thrombin and PAF were only partially inhibited. Agonists increased [Ca2+]i through release from internal stores and sustained Ca2+ influx. Thrombin stimulated Mn2+ influx, which was blocked by Ni2+. Diltiazem, isradipine, gramicidin and 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SK&F 96365) did not affect agonist-induced rises in [Ca2+]i. HEL cells contained substantial amounts of beta-glucuronidase which, however, could not be released, and they did not aggregate or generate superoxide. Our data suggest that: (1) HEL cells possess nucleotide receptors with properties similar to those of phagocytes; (2) they possess receptors for PGE2 and PGI2, and PGE1 is an agonist at both receptors; (3) agonist-induced increases in [Ca2+]i are mediated through pertussis toxin-sensitive as well as -insensitive signal transduction pathways; and (4) agonists increase [Ca2+]i by mobilization from internal stores and influx from the extracellular space through cation channels with properties similar to those of phagocytes and platelets.
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PMID:Receptor-mediated increases in cytosolic Ca2+ in the human erythroleukaemia cell line involve pertussis toxin-sensitive and -insensitive pathways. 131 May 89

The metabolism of the antiepileptic drug lamotrigine was characterized in human liver microsomes. For that purpose a high performance liquid chromatography method allowing the separation of lamotrigine glucuronide from the parent compound, and the quantitation of the glucuronide, was developed. The drug undergoes glucuronidation on the 2-nitrogen atom of the triazine ring, leading to a quaternary ammonium-linked glucuronide. This metabolite was positively identified from its hydrolysis by beta-glucuronidase and its associated radioactivity when UDP-[U-14C] glucuronic acid was used as the cosubstrate. Structural confirmation of the glucuronide was finally obtained by high performance liquid chromatography-mass spectrometry, by using a thermospray interface. The reaction proceeded with an apparent Vmax of 0.65 nmol/min/mg and Km of 2.56 mM. The average value of lamotrigine glucuronidation in four human samples of transplantable liver was 0.43 +/- 0.14 nmol/min/mg, thus indicating a large interindividual variation. An interspecies comparison of hepatic lamotrigine glucuronidation (human, rabbit, rat, monkey) revealed that the rate of glucuronidation was low. Of all the species considered, humans glucuronidated the drug to the greatest extent, with a specific activity 2-fold higher than that observed in rabbit liver microsomes. In contrast, the activity was greater than 20 times lower in monkey (0.019 nmol/min/mg) and at the limit of detection in rat liver microsomes. However, in this species, phenobarbital treatment enhanced lamotrigine glucuronidation slightly (0.017 nmol/min/mg). Among the drugs that undergo quaternary ammonium-linked glucuronidation, chlorpromazine, but not imipramine, amitriptyline and cyproheptadine, inhibited the glucuronidation of lamotrigine in vitro (IC50 of 5.0 x 10(-4) M).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro N-glucuronidation of a novel antiepileptic drug, lamotrigine, by human liver microsomes. 154 83

[3H]Benzo[a]pyrene (B[a]P) was administered to male Sprague-Dawley rats via intratracheal instillation, and bile was collected over a period of 6 h. Conjugated metabolites of B[a]P in bile were separated by paper chromatography or reversed-phase ion-pair HPLC and quantified by liquid scintillation spectrometry. In paper chromatographic analysis, a class of conjugates more polar than thioether conjugates was recognized. These conjugates were identified as quinol diglucuronides by hydrolyzing with beta-glucuronidase and analyzing products of the hydrolysis with HPLC, and by migration on paper relative to a standard of 3,6-quinol diglucuronide. From this analysis, relative amounts of conjugated metabolites of B[a]P in bile were 37.3% quinol diglucuronides, 19.9% thioether conjugates, 33.3% monoglucuronide and sulfate conjugates, and 9.4% unconjugated metabolites. Analysis by reversed-phase ion-pair HPLC provided improved resolution among the conjugates in bile. In particular, the 3,6-quinol diglucuronide was resolved from the 1,6- and 6,12-quinol diglucuronides, with identification of peaks being based on sensitivity to hydrolysis with beta-glucuronidase and elution of standards of these diglucuronides. The elution position of thioether conjugates was identified by their insensitivity to hydrolysis with beta-glucuronidase and arylsulfatase and by synthesis of thioether conjugates in V79 (XEM-2) cells, which express cytochrome P450IA1 and have relatively high levels of glutathione S-transferases but low levels of UDP-glucuronyltransferases and sulfotransferases. From the reversed-phase ion-pair HPLC analysis, relative amounts of conjugates in bile were 10.4% 1,6- and 6,12-quinol diglucuronides, 20.8% 3,6-quinol diglucuronide, 30.4% thioether conjugates, 17.8% monoglucuronides, 6.2% sulfate conjugates, and 14.4% unconjugated metabolites. These studies provide the first report of the biosynthesis of quinol diglucuronide conjugates of B[a]P in vivo and demonstrate that they are excreted into bile in significant quantities.
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PMID:Quinol diglucuronides are predominant conjugated metabolites found in bile of rats following intratracheal instillation of benzo[a]pyrene. 154 30

Long-chain fatty acids inhibit glucuronidation of benzo(a)pyrene phenols in perfused liver; therefore, this study was designed to investigate interactions of fatty acids with beta-glucuronidase, glucuronosyl transferase, and energy supply. In beta-glucuronidase-deficient C3H/He mice, infusion of oleate (250 microM) increased the release of free benzo(a)pyrene phenols from 14 to 33 nmol/g/h and decreased release of glucuronides into the perfusate from 25 to 17 nmol/g/h. Rates of accumulation of glucuronides in the liver were also diminished from 11 to 4 nmol/g/h after infusion of oleate (250 microM). Fatty acids did not affect the release of benzo(a)pyrene metabolites into bile, and the ratio of free phenol to glucuronide production was increased from 0.57 to 1.30. A similar trend was observed in livers from DBA/2 mice that have beta-glucuronidase. Rates of hydrolysis of benzo(a)pyrene-O-glucuronide were not altered in isolated microsomes by addition of oleoyl coenzyme A (CoA) or octanoyl CoA (10- approximately 100 microM). Thus, we conclude that fatty acids do not alter glucuronidation by acting on beta-glucuronidase. The concentration of cofactors (UDP-glucuronic acid, UDP-glucose, and adenine nucleotides) involved in hepatic conjugation was not altered by infusion of concentrations of oleate (300 microM) that inhibited glucuronidation in perfused livers. When oleate concentrations were increased to 600 microM, UDP-glucuronic acid and UDP-glucose decreased 44 and 49%, respectively, and the ATP:ADP ratio declined concomitantly. Oleoyl CoA inhibited UDP-glucuronosyl transferase noncompetitively (half-maximal inhibition, 10 microM) in microsomes with 3-hydroxy-benzo(a)pyrene or p-nitrophenol as substrate. In contrast, octanoyl CoA was a very poor inhibitor of transferase activity. Inhibition of the transferase by oleoyl CoA was increased markedly by treatment with detergents (Triton X-100), i.e., half-inhibition of glucuronosyl transferase was obtained with about 2 microM oleoyl CoA. Inhibition of UDP-glucuronosyl transferase by oleoyl CoA was also increased in a dose-dependent manner by albumin, possibly due to increasing access of the CoA derivative to the enzyme. Collectively, these data indicate that fatty acids diminish glucuronidation via the formation of acyl CoA compounds that inhibit UDP-glucuronosyl transferase noncompetitively.
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PMID:Inhibition of glucuronidation of benzo(a)pyrene phenols by long-chain fatty acids. 190 48

Whereas the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe), induced NADPH-oxidase-catalyzed superoxide (O2-) formation in human neutrophils, purine and pyrimidine nucleotides per se did not stimulate NADPH oxidase but enhanced O2- formation induced by submaximally and maximally stimulatory concentrations of fMet-Leu-Phe up to fivefold. On the other hand, FMet-Leu-Phe primed neutrophils to generate O2- upon exposure to nucleotides. At a concentration of 100 microM, purine nucleotides enhanced O2- formation in the effectiveness order adenosine 5'-O-[3-thio]triphosphate (ATP[gamma S]) greater than ITP greater than guanosine 5'-O-[3-thio]triphosphate (GTP[gamma S]) greater than ATP = adenosine 5'-O-[2-thio]triphosphate (Sp-diastereomer) = GTP = guanosine 5'-O-[2-thio]diphosphate (GDP[beta S] = ADP greater than adenosine 5'-[beta, gamma-imido]triphosphate = adenosine 5'-O-[2-thio]triphosphate] (Rp-diastereomer). Pyrimidine nucleotides stimulated fMet-Leu-Phe-induced O2- formation in the effectiveness order uridine 5'-O-[3-thio]triphosphate (UTP[gamma S]) = UTP greater than CTP. Uracil (UDP[beta S]) = uridine 5'-O[2-thio]triphosphate (Rp-diastereomer) (Rp)-UTP[beta S]) = UTP greater than CTP. Uracil nucleotides were similarly effective potentiators of O2- formation as the corresponding adenine nucleotides. GDP[beta S] and UDP[beta S] synergistically enhanced the stimulatory effects of ATP[gamma S], GTP[gamma S] and UTP[gamma S]. Purine and pyrimidine nucleotides did not induce degranulation in neutrophils but potentiated fMet-Leu-Phe-induced release of beta-glucuronidase with similar nucleotide specificities as for O2- formation. In contrast, nucleotides per se induced aggregation of neutrophils. Treatment with pertussis toxin prevented aggregation induced by both nucleotides and fMet-Leu-Phe. Our results suggest that purine and pyrimidine nucleotides act via nucleotide receptors, the nucleotide specificity of which is different from nucleotide receptors in other cell types. Neutrophil nucleotide receptors are coupled to guanine-nucleotide-binding proteins. As nucleotides are released from cells under physiological and pathological conditions, they may play roles as intercellular signal molecules in neutrophil activation.
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PMID:Purine and pyrimidine nucleotides potentiate activation of NADPH oxidase and degranulation by chemotactic peptides and induce aggregation of human neutrophils via G proteins. 254 Sep 69

Functional state of enzymatic systems in rat liver endoplasmic reticulum was studied. Content of cytochromes P-450 and b5 as well as activities of UDP-glucuronyl transferase, glucose-6-phosphatase, beta-glucuronidase, acetylesterase, inosine-5-diphosphatase were evaluated after permanent administration of nitrosodimethylamine within 2, 5 and 10 months at concentrations of 0.1, 1.0 and 10.0 mg/l. Content of the cancerogene active metabolites in liver cells was shown to be responsible for impairment of the functional state of microsomal enzymatic systems and was also related to intensity and duration of the nitrosodimethylamine effect. The level of these cancerogene metabolites in liver cells depended on rates of the cancerogene oxidation in the monooxygenase system and elimination of active products. At the same time, the rate of nitrosodimethylamine metabolism correlated with the doses of the substance administered into rats.
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PMID:[Effect of low concentrations of nitrosodimethylamine on the functional state of enzymatic systems in the endoplasmatic reticulum of the rat liver]. 283 31

Studies on the induction of non-oxygenative detoxication enzymes in mice by anticarcinogenic thionosulfur compounds have been extended to include hepatic and pulmonary UDP-glucuronosyltransferases. Dietary administration of disulfiram and of bisethylxanthogen to female CD-1 mice enhanced microsomal glucuronidation of 4-methylumbelliferone, a characteristic GT1 substrate, and of 4-hydroxybiphenyl, a GT2 substrate. Latency of the activity toward 4-methylumbelliferone was not affected appreciably. Disulfiram also enhanced glucuronidation of 4-nitrophenol. Diethyldithiocarbamate was ineffective under the conditions used. These thionosulfur compounds caused no significant change in beta-glucuronidase activity measured in homogenates of 7 organs.
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PMID:Differential responses of mouse UDP-glucuronosyltransferases and beta-glucuronidase to disulfiram and related compounds. 283 96


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