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)

Microsomal fraction contains the whole of hepatic UDP-glucuronyltransferase as well as part of beta-glucuronidase. The activities of the two enzymes were assayed under identical conditions using untreated male rat liver microsomes at pH 7.5. In a 30-min incubation with p-nitrophenol and UPD-glucuronic acid, a net glucuronide formation of 0.010 mumol.min-1.g.liver-1 was measured. In the presence of saccharolactone at concentrations selectively blocking beta-glucuronidase, the glucuronidation rate was 0.015 mumol.min-1.g.liver-1. Using the kinetic parameters of beta-glucuronidase (Km = 0.06 mmol/l p-nitrophenylglucuronide, Vm = 0.075 mumol pNP formed.h-1.g.liver-1) determined in the absence of UDP-glucuronic acid, to correct for the beta-glucuronidase's interference on the glucuronidation process, a glucuronide formation of 0.011 mumol.min-1.g.liver-1 was calculated.
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PMID:Interference of UDP-glucuronyltransferase and beta-glucuronidase activity in rat liver microsomes at pH 7.5 with p-nitrophenol and p-nitrophenylglucuronide as substrates. 3 49

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

Verlukast, (S)3-((((3-(2-(7-chloroquinolin-2-yl)-(E)-ethenyl)phenyl)- 3-dimethylamino-3-oxopropylthio)methyl)thio)propionic acid, formerly known as MK-679, is a potent leukotriene D4 antagonist. Verlukast was incubated with rat liver microsomes under oxidative conditions to generate five metabolites, which were identified as the four possible isomeric monosulfoxides (M1-M4), and the N-hydroxymethyl amide (M5). This latter metabolite loses the elements of formaldehyde to yield the N-monomethyl amide (M6). These metabolites were isolated from a large microsomal incubation and were characterized by UV, 1H-NMR, and fast atom bombardment-MS. These data were identical to those obtained from synthetically prepared standards. Microsomal incubations of verlukast supplemented with UDP-glucuronic acid yielded the acyl glucuronide metabolite (M7), which was isolated and characterized by UV, 1H-NMR, and fast atom bombardment-M5. Verlukast was regenerated from M7 upon treatment with either beta-glucuronidase or strong aqueous base (pH greater than 11). The metabolites described above were all detected in bile collected from a rat dosed with verlukast.
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PMID:In vitro and in vivo biotransformations of the potent leukotriene D4 antagonist verlukast in the rat. 135 12

In isolated rat hepatocytes, cadmium (0-200 microM) decreased the overall glucuronidation of both isopropyl N-(3-chloro-4 hydroxyphenyl)carbamate (4-hydroxychlorpropham, 4-OHCIPC) and 4-nitrophenol in a concentration-dependent manner. In contrast, in native rat liver microsomes, glucuronidation of 4-OHCIPC was increased by cadmium through activation of microsomal 4-OHCIPC glucuronosyl transferase. In addition, in rat microsome incubations, the net amount of 4-OHCIPC glucuronide was also indirectly increased by cadmium through a reduction in the activity of beta-glucuronidase. As the effect of cadmium on the activity of 4-OHCIPC glucuronosyl transferase could not account for the decrease in glucuronide formation in intact hepatocytes, the influence of cadmium on the availability of UDP-glucuronic acid (UDPGA) was investigated further. In isolated rat hepatocytes, cadmium depleted the UDPGA content in a dose-dependent manner without a change in the UDP glucose (UDPG) content. Cadmium did not increase the breakdown of UDPGA by microsomal UDPGA pyrophosphatase but strongly decreased (30-66%) the synthesis of the cofactor in the cytosol by inhibiting UDP-glucose dehydrogenase (UDPGDH). Cadmium (10-50 microM) was found to inhibit the purified enzyme from bovine liver (EC 1.1.1.22) non-competitively. In vivo in the absence of a substrate undergoing glucuronidation, cadmium administration, 1.5 and 2.5 mg Cd/kg i.v., to normally fed rats resulted in a 15 and 30% decrease of hepatic UDPGA, respectively. However, in the liver, neither the NAD+/NADH ratio nor the UDPG content was significantly changed following cadmium treatment. Both in vitro and in vivo results support the conclusion that in intact cells the reduction in overall 4-OHCIPC glucuronidation caused by cadmium was due to a decrease in UDPGA availability which results from the inhibiting effect of cadmium on UDPGDH.
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PMID:Mechanism of cadmium-decreased glucuronidation in the rat. 147 79

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

A major metabolite of zidovudine (3'-azido-3'-deoxythymidine, AZT), which previously had not been observed in a variety of experimental animals, was identified in samples of plasma and urine from cynomolgus monkeys and a patient treated with AZT. The urinary recoveries of metabolite from the monkeys and the patient were, respectively, 1.5- and 6.9-fold higher than the recoveries of unchanged drug. The metabolite was purified in gram quantities from the urines of the monkeys and the patient and was identified enzymatically, using beta-glucuronidase and a specific inhibitor of the enzyme, as a glucuronide conjugate of AZT. The metabolite was formed in vitro by incubating AZT with preparations of human liver in the presence of UDP-glucuronic acid. In addition, the metabolite was prepared synthetically and physical characterizations--including microanalysis and UV, IR, NMR and mass spectra--of compound from all three sources were identical and confirmed the metabolite to be the 5'-O-beta-D-glucuronide of AZT.
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PMID:Isolation and characterization of an ether glucuronide of zidovudine, a major metabolite in monkeys and humans. 197 93

A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on hepatic glucuronidation activity. As was previously observed with hepatic oxidative drug metabolism, model trauma resulted in a significant decrease in the in vivo glucuronidation of chloramphenicol, with a 23% drop in clearance of this drug. The effect on in vivo pharmacokinetics appeared to result from a complex interaction between trauma's differential influences on conjugating enzyme(s), deconjugating enzyme(s), and hepatic UDP-glucuronic acid levels, as well as the relative physiological importance of these variables. Hepatic UDP-glucuronyltransferase activities towards both p-nitrophenol and chloramphenicol were elevated (44-54%) after model injury when measured in native hepatic microsomes. However, microsomes which had been "activated" by treatment with Triton X-100 showed no significant difference between control and traumatized animals. Serum beta-glucuronidase activities were elevated by 58%, while hepatic beta-glucuronidase rose by about 16%. Nevertheless, in vivo deconjugation showed no significant change. Model trauma also resulted in a 46% decrease in hepatic UDP-glucuronic acid content. Thus, the observed post-traumatic depression of in vivo chloramphenicol glucuronidation could be due either to a diminished availability of a necessary cofactor (UDP-glucuronic acid) or to an alteration in enzyme kinetics or function in vivo.
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PMID:Effects of model traumatic injury on hepatic drug metabolism in the rat. IV. Glucuronidation. 286

A biosynthetic acyl-type glucuronic acid conjugate of furosemide was isolated from in vitro incubation of pregnenolone-16 alpha-carbonitrile-induced rat liver microsomes containing UDP-glucuronyltransferase activity, furosemide, and UDP-glucuronic acid. Furosemide 1-O-acyl glucuronide (FG) was specifically hydrolyzed by beta-glucuronidase (BG) and was also labile to alkaline hydrolysis. FG concentration decreased at an apparent first order rate when incubated at 37 degrees C in buffer solution of pH values greater than 6.0 with only moderate hydrolysis of the conjugate at pH values less than 8.5. Formation of rearrangement forms of FG that were resistant to BG but labile to alkaline hydrolysis accounted for most of the disappearance of FG at this pH range. Radiochemical labeling of the conjugate with either 14C-furosemide or 14C-UDP-glucuronic acid was detected in the BG-resistant isomerization products of FG as they were separated by HPLC. The structure of FG and its isomerization products was further verified by negative ion thermospray liquid chromatography/mass spectrometry. The abundant (M - 1)-ion at mass 505, the aglycone fragment at m/z 329, and the characteristic sugar fragment ion of mass 175 were found in the spectra of FG and three additional isomers. An ion at m/z 221 was noted only in the case of the parent conjugate and thus may prove to be a characteristic ion for 1-O-acyl-linked glucuronides under negative ion thermospray. In vivo as well as in vitro rearrangement of FG to BG-resistant forms might affect the results of furosemide disposition studies which use BG hydrolysis to determine FG formation.
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PMID:Furosemide 1-O-acyl glucuronide. In vitro biosynthesis and pH-dependent isomerization to beta-glucuronidase-resistant forms. 286 75

Dibutyryl cyclic adenosine 3':5'-monophosphate (DBcAMP) has been reported to cause numerous alterations in the activity of hepatic monooxygenase enzymes following in vivo administration or in vitro addition to intact liver preparations. In the present report the effect of the nucleotide on metabolism of p-nitroanisole (pNA) and aniline was studied in isolated rat hepatocytes. Initial studies indicated that in vitro addition of DBcAMP to hepatocytes increased metabolism of both pNA and aniline as determined by the production of oxidized metabolites, p-nitrophenol (pNP) and p-aminophenol, respectively. After enzymatic hydrolysis with beta-glucuronidase and arylsulfatase, it was determined that DBcAMP had increased accumulation of pNP formed from pNA by inhibiting further metabolism via conjugation reactions. Further studies using pNP directly as substrate confirmed the finding and revealed that glucuronidation was more sensitive to the inhibitory effect of DBcAMP than was sulfation. The 8-bromo derivative of cAMP was more potent than DBcAMP at inhibiting glucuronidation, whereas cyclic AMP and dibutyryl cyclic guanosine 3':5'-monophosphate were without effect. Noncyclic adenine nucleotides (ATP, ADP, AMP) also altered pNA and pNP metabolism. ATP and ADP increased pNP accumulation from pNA while ATP and AMP inhibited glucuronidation of pNP. DBcAMP was further found to decrease UDP-glucuronic acid levels in a concentration-dependent manner without disrupting the redox state (NAD+/NADH) in hepatocytes. The data suggest that adenine nucleotides exert a nonspecific inhibition upon glucuronidation and sulfation reactions.
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PMID:Inhibition of glucuronidation and sulfation by dibutyryl cyclic AMP in isolated rat hepatocytes. 287 57


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