Contribution of the Different UDP-Glucuronosyltransferase (UGT) Isoforms to Buprenorphine and Norbuprenorphine Metabolism and Relationship with the Main UGT Polymorphisms in a Bank of Human Liver Microsomes

@article{Rouguieg2010ContributionOT,
  title={Contribution of the Different UDP-Glucuronosyltransferase (UGT) Isoforms to Buprenorphine and Norbuprenorphine Metabolism and Relationship with the Main UGT Polymorphisms in a Bank of Human Liver Microsomes},
  author={Koukeb Rouguieg and Nicolas Picard and François Ludovic Sauvage and Jean-michel Gaulier and Pierre Marquet},
  journal={Drug Metabolism and Disposition},
  year={2010},
  volume={38},
  pages={40 - 45}
}
The goal of this study was to evaluate the specific contribution of individual UDP-glucuronosyltransferase (UGT) isoforms in the metabolism of buprenorphine (BUP) and norbuprenorphine (Nor-BUP), as well as the impact of their genetic variations. The glucuronidation of BUP and Nor-BUP was examined using human liver microsomes (HLMs) and heterologously expressed UGTs. The individual contribution of UGT isoforms was estimated using enzyme kinetic experiments combined with the relative activity… 

Tables from this paper

Main contribution of UGT1A1 and CYP2C9 in the metabolism of UR-1102, a novel agent for the treatment of gout
TLDR
UR-1102, a novel uricosuric agent for treating gout, has been confirmed to exhibit a pharmacological effect in patients and its metabolic pathway was clarified, the contribution of each metabolic enzyme was estimated, and the impact of genetic polymorphisms using human in vitro materials was assessed.
Involvement of UDP-Glucuronosyltransferases UGT1A9 and UGT2B7 in Ethanol Glucuronidation, and Interactions with Common Drugs of Abuse
TLDR
The results suggest that cannabinol and cannabidiol could significantly alter ethanol glucuronidation, and UGT1A9 and 2B7 are the main enzymes involved in ethanol glucuridation.
Glucuronidation of macelignan by human liver microsomes and expressed UGT enzymes: identification of UGT1A1 and 2B7 as the main contributing enzymes
TLDR
It was shown that UGT1A1 and 2B7 were probably the main contributors to the hepatic glucuronidation of macelignan, and was efficiently metabolized via the glucuronidated pathway.
Characterization of Hepatic and Intestinal Glucuronidation of Magnolol: Application of the Relative Activity Factor Approach to Decipher the Contributions of Multiple UDP-Glucuronosyltransferase Isoforms
TLDR
The RAF approach can be used as an efficient method for deciphering the roles of individual UGTs in a given glucuronidation pathway in the native tissue that is catalyzed by multiple isoforms with variable and atypical kinetics.
Regio- and isoform-specific glucuronidation of psoralidin: evaluation of 3-o-glucuronidation as a functional marker for UGT1A9.
TLDR
Psoralidin was subjected to efficient glucuronidation, generating one or two monoglucuronides depending on UGT isozymes, and was an excellent in vitro marker for UGT1A9.
Glucuronidation of capsaicin by liver microsomes and expressed UGT enzymes: reaction kinetics, contribution of individual enzymes and marked species differences
TLDR
Capsaicin was subjected to significant hepatic glucuronidation, wherein UGT1A1 and 2B7 were the main contributing enzymes.
Involvement of UDPGlucuronosyltransferases UDPGlucuronosyltransferases UDPGlucuronosyltransferases UGT 1 A 9 and UGT 2 B 7 in Ethanol Glucuronidation , and Interactions with Common Drugs of Abuse
TLDR
The results suggest that cannabinol and cannabidiol could significantly alter ethanol, and UGT1A9 and 2B7 are the main enzymes involved in ethanol glucuronidation.
Human UGT2B7 is the major isoform responsible for the glucuronidation of clopidogrel carboxylate
TLDR
Results reveal that UGT2B7 is the major enzyme catalyzing clopidogrel glucuronidation in the human liver, and that there is the potential for drug‐drug interactions between clopinogrel and the other substrate drugs of UGT 2B7.
In Vitro Characterization of Ertugliflozin Metabolism by UDP-Glucuronosyltransferase and Cytochrome P450 Enzymes
TLDR
The use of orthogonal approaches to characterize the fraction of ertugliflozin metabolism through various UDP-glucuronosyltransferase (UGT) and cytochrome P450 enzyme-mediated pathways allows risk assessment when considering potential victim-based drug-drug interactions perpetrated by coadministered drugs.
Regioselective Glucuronidation of Tanshinone IIa after Quinone Reduction: Identification of Human UDP-Glucuronosyltransferases, Species Differences, and Interaction Potential
TLDR
TSA presented a potent inhibitory effect on the glucuronidation of typical UGT1A9 substrates propofol and mycophenolic acid, with an IC50 value of 8.4 ± 1.8 and 8.8 μl/min/mg protein, respectively, which will help to guide future studies on characterizing the NQO1-mediated reduction and subsequent glucuronidated of other quinones.
...
...

References

SHOWING 1-10 OF 46 REFERENCES
Limited influence of UGT1A1*28 and no effect of UGT2B7*2 polymorphisms on UGT1A1 or UGT2B7 activities and protein expression in human liver microsomes.
TLDR
Data indicate only a partial (approximately 40%) contribution of the UGT1A1*28 polymorphism to variability of interindividual differences in UGT 1A1 enzyme activity.
Glucuronidation of etoposide in human liver microsomes is specifically catalyzed by UDP-glucuronosyltransferase 1A1.
TLDR
Results demonstrate that etoposide glucuronidation in human liver microsomes is specifically catalyzed by UGT1A1, and according to the derivatization with trimethylsilylimidazole (Tri-Sil-Z), it was confirmed that the glucuronic acid is linked to an alcoholic hydroxyl group of etopside and not to a phenolic group.
Prediction of Drug Clearance by Glucuronidation from in Vitro Data: Use of Combined Cytochrome P450 and UDP-Glucuronosyltransferase Cofactors in Alamethicin-Activated Human Liver Microsomes
TLDR
The applicability of combined cofactor conditions in the assessment of clearance for compounds with a differential contribution of P450 and UGT enzymes to their elimination is indicated, in particular for UGT2B7 substrates.
Glucuronidation activity of the UGT2B17 enzyme toward xenobiotics.
TLDR
The characterization of UGT2B17 as a xenobiotics-conjugating enzyme demonstrates that its role is not limited to androgen metabolism and that its specificity for exogenous substrates is different from other UGT 2B isoforms.
The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268).
TLDR
UGT2B7 seems to be a major human isoform responsible for the glucuronidation of opioids of the morphinan and oripavine class and is capable of catalyzing the glucuridation of both the 3- and 6-hydroxyl moieties on these molecules.
Comparison of stably expressed rat UGT1.1 and UGT2B1 in the glucuronidation of opioid compounds.
TLDR
The results suggest that opioids with morphinan-basedchemical structures similar to (-)-morphine interact with UGTs differently than those with oripavine-based chemical structures such to buprenorphine.
Glucuronidation of catechol estrogens by expressed human UDP-glucuronosyltransferases (UGTs) 1A1, 1A3, and 2B7.
  • Z. Cheng, G. Rios, T. Tephly
  • Biology, Chemistry
    Toxicological sciences : an official journal of the Society of Toxicology
  • 1998
TLDR
The results suggest that drug-endobiotic interactions are possible in humans and may have implication in carcinogenesis and 2-hydroxycatechol estrogens react with separate active sites of UGT1A3.
The glucuronidation of exogenous and endogenous compounds by stably expressed rat and human UDP-glucuronosyltransferase 1.1.
TLDR
Rat and human UDP-glucuronosyltransferase (UGT) 1.1 are functionally identical and can be considered orthologous enzymes, according to the results of the present study.
UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations.
TLDR
High prevalence of highly prevalent polymorphisms, which result in modified expression and activity of UGTs, may influence susceptibility to cancers associated with altered metabolism of endogenous and xenobiotic compounds.
...
...