Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.31 (beta-glucuronidase)
 7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acyl glucuronides are a unique class of electrophilic metabolites, capable of non-enzymatic reactions including acylation and/or glycation of endogenous macromolecules, hydrolysis to reform the parent aglycone, and intra-molecular rearrangement. Three human UDP-glucuronosyltransferases (UGTs) catalyzing the hepatic glucuronidation of carboxylic acid drugs have been identified, UGT1A3, UGT1A9 and a UGT2B7 variant. Within the liver, acyl glucuronides also undergo enzymatic hydrolysis by beta-glucuronidase and esterases which, like the UGTs, are located in the endoplasmic reticulum. In addition, the liver also transports acyl glucuronides between the sinusoidal circulation and bile. Due to their polarity, membrane transport of acyl glucuronides is carrier-mediated, resulting in the establishment of significant concentration gradients between sinusoidal circulation, hepatocyte and bile, in the order of 1:50:5,000 in these compartments, respectively. As a result of exposure to high acyl glucuronide concentrations, the liver is a major target of protein adduct formation. Dipeptidylpeptidase IV, UGTs and tubulin have been identified as intra-hepatic targets of adduct formation by acyl glucuronides. Adduct formation results in altered protein activity and potentially contributes to hepatotoxicity. Hepatic protein adducts are also immunogenic and may cause immune mediated cytotoxicity. Both intra- and extra-hepatic exposure to acyl glucuronides depends not only on the efficiency of glucuronidation and hydrolysis by the liver, but also on the efficiency of the hepatic membrane transport systems. Thus, changes in membrane transporter activities, as may occur due to saturation or drug-drug interactions, can significantly affect acyl glucuronide disposition, adduct formation and the disposition of parent aglycone, thereby affecting clinical efficacy and toxicity of acyl glucuronide forming drugs.
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PMID:Hepatic disposition of electrophilic acyl glucuronide conjugates. 1146 81

1. The antitumour agent bropirimine undergoes significant Phase II conjugation in vivo. Incubation of [14C]bropirimine with human liver microsomes resulted in the formation of a single product peak (M1) using high-performance liquid chromatography with radiochemical detection and was tentatively assigned as bropirimine glucuronide based on sensitivity to beta-glucuronidase and by obtaining the expected mass of 442/444 amu with liquid chromatography/mass spectrometry. Following metabolite isolation, the structure of M1 was established as bropirimine O-glucuronide by 1H-nuclear magnetic spectroscopy. 2. Studies aimed at identifying the human liver UDP-glucuronosyltransferase (UGT) enzyme(s) involved in the glucuronidation of bropirimine were carried out using recombinant human UGTs and it was determined that glucuronidation of bropirimine was catalysed by UGT1A1, UGT1A3 and UGT1A9. Bropirimine O-glucuronidation followed Michaelis-Menten kinetics and the Km and Vmax (mean +/- SD; n = 3) were 1217 +/- 205 microM and 667 +/- 188 pmol min(-1) mg(-1), respectively. 3. The activity of bropirimine O-glucuronidation by human liver microsomes was inhibited by bilirubin (40%) and with mefenamic acid (80%). Although buprenorphine extensively inhibited the activity of bropirimine O-glucuronidation by UGT1A3, the inhibition profile did not parallel that observed in HLMs. 4. The results demonstrate that UGT1A9 and to a lesser extent UGT1A1 are responsible for the majority of bropirimine O-glucuronidation in man.
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PMID:Characterization of bropirimine O-glucuronidation in human liver microsomes. 1455 37

The potential cancer therapeutic agent, 6,7-(dimethoxy-2, 4-dihydroindeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (JNJ-10198409), formed three N-glucuronides that were positively identified by liquid chromatography-tandem mass spectrometry and NMR as N-amine-glucuronide (Glu-A), 1-N-pyrazole-glucuronide (Glu-B), and 2-N-pyrazole-glucuronide (Glu-C). All three N-glucuronides were detected in rat liver microsomes, whereas only Glu-A and -B were found in monkey and human liver microsomes. In contrast to common glucuronides, Glu-B was completely resistant to beta-glucuronidase. Kinetic analyses revealed that glucuronidation of JNJ-10198409 in human liver microsomes exhibited atypical kinetics that may be described by a two-site binding model. For the high affinity binding, K(m) values were 1.2 and 5.0 microM, and V(max) values were 2002 and 2,403 nmol min(-1) mg(-1) for Glu-A and Glu-B, respectively. Kinetic constants of low affinity binding were not determined due to low solubility of the drug. Among the human UDP-glucuronosyltransferases (UGTs) tested, UGT1A9, 1A8, 1A7, and 1A4 were the most active isozymes to produce Glu-A; for the formation of Glu-B, UGT1A9 was the most active enzyme, followed by UGT1A3, 1A7, and 1A4. Glucuronidation of JNJ-10198409 by those UGT1A enzymes followed classic Michaelis-Menten kinetics. In contrast, no glucuronides were formed by all UGT2B isozymes tested, including UGT2B4, 2B7, 2B15, and 2B17. Collectively, these results suggested that glucuronidation of JNJ-10198409 in human liver microsomes is catalyzed by multiple UGT1A enzymes. Since UGT1A enzymes are widely expressed in various tissues, it is anticipated that both hepatic and extrahepatic glucuronidation will likely contribute to the elimination of the drug in humans. Additionally, conjugation at the nitrogens of the pyrazole ring represents a new structural moiety for UGT1A-mediated reactions.
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PMID:N-glucuronidation of the platelet-derived growth factor receptor tyrosine kinase inhibitor 6,7-(dimethoxy-2,4-dihydroindeno[1,2-C]pyrazol-3-yl)-(3-fluoro-phenyl)-amine by human UDP-glucuronosyltransferases. 1645 2

Mitiglinide (MGN) is a new potassium channel antagonist for the treatment of type 2 diabetes mellitus. In the present study, a potential metabolic pathway of MGN, via carboxyl-linked glucuronic acid conjugation, was found. MGN carboxyl-glucuronide was isolated from a reaction mixture consisting of MGN and human liver microsomes fortified with UDP-glucuronic acid (UDPGA) and identified by a hydrolysis reaction with beta-glucuronidase and HPLC-MS/MS. Kinetic analysis indicated that MGN from four species had the highest affinity for the rabbit liver microsomal enzyme (K(m)=0.202 mM) and the lowest affinity for the dog liver microsomal enzyme (K(m)=1.164 mM). The metabolic activity (V(max)/K(m)) of MGN to the carboxyl-glucuronidation was in the following order: rabbit>dog>rat>human. With the assessment of MGN glucuronide formation across a panel of recombinant UDP-glucuronosyltransferase (UGT) isoforms (UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7), only UGT1A3 and UGT2B7 exhibited high MGN glucuronosyltransferase activity. The K(m) values of MGN glucuronidation in recombinant UGT1A3 and UGT2B7 microsomes were close to those in human liver microsomes. The formation of MGN glucuronidation by human liver microsomes was effectively inhibited by quercetin (substrate for UGT1A3) and diclofenac (substrate for UGT2B7), respectively. The MGN glucuronidation activities in 15 human liver microsomes were significantly correlated with quercetin (r(2)=0.806) and diclofenac glucuronidation activities (r(2)=0.704), respectively. These results demonstrate that UGT1A3 and UGT2B7 are catalytic enzymes in MGN carboxyl-glucuronidation in human liver.
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PMID:Carboxyl-glucuronidation of mitiglinide by human UDP-glucuronosyltransferases. 1735 41

Stereoselective glucuronidation of propafenone and its beta-blocker analogues by human recombinant UGT1A3 and UGT1A9 from the recombinant baculovirus in insect sf9 cells was studied. The glucuronides produced in incubation mixtures were assayed by HPLC equipped with UV detector, and identified by beta-glucuronidase. The stereoselective glucuronidation was measured by pre-column 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocynate (GITC) derivatization HPLC method for propafenone and esomolol. In all of ten beta-blocker drugs studied, six showed the glucuronidation activity with UGT1A9, while four with UGT1A3. From roughly quantitative stereoselective glucuronidation study of racemic beta-blocker analogues by UGT1A9, propranolol had a high ratio of the ratios of S- to R-isomer glucuronide (S-G/R-G), about 4.3, the ratios of terbutaline, atenolol and esomolol were 3.3, 3.1 and 2.8 respectively, sotalol and propafenone were 2.3 and 2.0. In a word, S-isomers of these drugs were glucuronidated by human UGT1A9 much faster than their antipodes.
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PMID:Stereoselective glucuronidation of propafenone and its analogues by human recombinant UGT1A9. 2052 6