REGIOSELECTIVE GLUCURONIDATION OF DENOPAMINE: MARKED SPECIES DIFFERENCES AND IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ISOFORM
- 1 March 2005
- journal article
- research article
- Published by Elsevier in Drug Metabolism and Disposition
- Vol. 33 (3) , 403-412
- https://doi.org/10.1124/dmd.104.002667
Abstract
Denopamine is one of the oral β1-adrenoceptor-selective partial agonists. Denopamine glucuronide is the most abundant metabolite in human, rat, and dog urine when administered orally. Species differences in denopamine glucuronidation were investigated with liver microsomes obtained from humans and experimental animals. In rat and rabbit, only the phenolic glucuronide was detected, whereas in dog and monkey, not only the phenolic glucuronide but also the alcoholic glucuronide was found. In contrast, in humans, the alcoholic glucuronide was detected exclusively. The kinetics of denopamine glucuronidation in human liver microsomes showed a typical Michaelis-Menten plot. The Km and Vmax values accounted for 2.87 ± 0.17 mM and 7.29 ± 0.23 nmol/min/mg protein, respectively. With the assessment of denopamine glucuronide formation across a panel of recombinant UDP-glucuronosyltransferase (UGT) isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15, and UGT2B17), only UGT2B7 exhibited high denopamine glucuronosyltransferase activity. The Km value of denopamine glucuronidation in recombinant UGT2B7 microsomes was close to those in human liver and jejunum microsomes. The formation of denopamine glucuronidation by human liver, jejunum, and recombinant UGT2B7 microsomes was effectively inhibited by diclofenac, a known substrate for UGT2B7. The denopamine glucuronidation activities in seven human liver microsomes were significantly correlated with diclofenac glucuronidation activities (r2 = 0.685, p < 0.05). These results demonstrate that the denopamine glucuronidation in human liver and intestine is mainly catalyzed by UGT2B7 and that glucuronidation of the alcoholic hydroxyl group, but not the phenolic hydroxyl group, occurs regioselectively in humans.Keywords
This publication has 25 references indexed in Scilit:
- CHARACTERIZATION OF AFLOQUALONE N-GLUCURONIDATION: SPECIES DIFFERENCES AND IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ISOFORM(S)Drug Metabolism and Disposition, 2005
- IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ENZYME(S) RESPONSIBLE FOR THE GLUCURONIDATION OF EZETIMIBE (ZETIA)Drug Metabolism and Disposition, 2004
- EVALUATION OF 3′-AZIDO-3′-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7*2 POLYMORPHISMDrug Metabolism and Disposition, 2003
- Simultaneous Expression of Guinea Pig UDP-Glucuronosyltransferase 2B21 and 2B22 in COS-7 Cells enhances UDP-Glucuronosyltransferase 2B21-Catalyzed Morphine-6-Glucuronide FormationMolecular Pharmacology, 2001
- The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism*†Drug Metabolism Reviews, 2001
- Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significancePharmacogenetics, 2000
- Protein−Protein Interactions between UDP-Glucuronosyltransferase Isozymes in Rat Hepatic MicrosomesBiochemistry, 1997
- Use of In Vitro and In Vivo Data to Estimate the Likelihood of Metabolic Pharmacokinetic InteractionsClinical Pharmacokinetics, 1997
- The Glucuronidation of Exogenous and Endogenous Compounds by Stably Expressed Rat and Human UDP-Glucuronosyltransferase 1.1Archives of Biochemistry and Biophysics, 1996
- Radiation inactivation analysis of microsomal UDP-glucuronosyltransferases catalysing mono-and diglucuronide formation of 3,6-dihydroxybenzo(a)pyrene and 3,6-dihydroxychryseneBiochemical Pharmacology, 1994