UDP-Glucuronosyltransferase (UGT)-mediated attenuations of cytochrome P450 3A4 activity: UGT isoform-dependent mechanism of suppression.
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
20
01
2018
revised:
19
09
2019
accepted:
28
09
2019
pubmed:
30
10
2019
medline:
22
6
2021
entrez:
30
10
2019
Statut:
ppublish
Résumé
Cytochrome P450 (CYP, P450) 3A4 is involved in the metabolism of 50% of drugs and its catalytic activity in vivo is not explained only by hepatic expression levels. We previously demonstrated that UDP-glucuronosyltransferase (UGT) 2B7 suppressed CYP3A4 activity through an interaction. In the present study, we target UGT1A9 as another candidate modulator of CYP3A4. We prepared co-expressed enzymes using the baculovirus-insect cell expression system and compared CYP3A4 activity in the presence and absence of UGT1A9. Wistar rats were treated with dexamethasone and liver microsomes were used to elucidate the role of CYP3A-UGT1A interactions. UGT1A9 and UGT2B7 interacted with and suppressed CYP3A4. Kinetic analyses showed that both of the UGTs significantly reduced V The changes of kinetic parameters suggested that UGT1A9 suppressed CYP3A4 activity with almost the same mechanism as UGT2B7. The luminal domain of UGTs contains the suppressive interaction site(s), whereas the C-terminal domain may contribute to modulating suppression in a UGT isoform-specific manner. CYP3A-UGT1A interaction seemed to be disturbed by dexamethasone treatment and the suppression was partially cancelled. CYP3A4-UGT interactions would help to better understand the causes of inter/intra-individual differences in CYP3A4 activity.
Sections du résumé
BACKGROUND AND PURPOSE
Cytochrome P450 (CYP, P450) 3A4 is involved in the metabolism of 50% of drugs and its catalytic activity in vivo is not explained only by hepatic expression levels. We previously demonstrated that UDP-glucuronosyltransferase (UGT) 2B7 suppressed CYP3A4 activity through an interaction. In the present study, we target UGT1A9 as another candidate modulator of CYP3A4.
EXPERIMENTAL APPROACH
We prepared co-expressed enzymes using the baculovirus-insect cell expression system and compared CYP3A4 activity in the presence and absence of UGT1A9. Wistar rats were treated with dexamethasone and liver microsomes were used to elucidate the role of CYP3A-UGT1A interactions.
KEY RESULTS
UGT1A9 and UGT2B7 interacted with and suppressed CYP3A4. Kinetic analyses showed that both of the UGTs significantly reduced V
CONCLUSION AND IMPLICATIONS
The changes of kinetic parameters suggested that UGT1A9 suppressed CYP3A4 activity with almost the same mechanism as UGT2B7. The luminal domain of UGTs contains the suppressive interaction site(s), whereas the C-terminal domain may contribute to modulating suppression in a UGT isoform-specific manner. CYP3A-UGT1A interaction seemed to be disturbed by dexamethasone treatment and the suppression was partially cancelled. CYP3A4-UGT interactions would help to better understand the causes of inter/intra-individual differences in CYP3A4 activity.
Identifiants
pubmed: 31660580
doi: 10.1111/bph.14900
pmc: PMC7042106
doi:
Substances chimiques
Protein Isoforms
0
Cytochrome P-450 CYP3A
EC 1.14.14.1
Glucuronosyltransferase
EC 2.4.1.17
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1077-1089Subventions
Organisme : Japan Society for the Promotion of Science
ID : 25293039
Pays : International
Organisme : Ministry of Education, Culture, Sports, Science and Technology
ID : 19590147
Pays : International
Organisme : Japan Research Foundation for Clinical Pharmacology
Pays : International
Informations de copyright
© 2019 The British Pharmacological Society.
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