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UDP-Glucuronosyltransferase (UGT)-mediated attenuations of cytochrome P450 3A4 activity: UGT isoform-dependent mechanism of suppression.

Abstract：

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 Vmax of CYP3A4 activity. In addition, C-terminal truncated mutants of UGT1A9 and UGT2B7 still retained the suppressive capacity. Dexamethasone treatment induced hepatic CYP3As and UGT1As at different magnitudes. Turnover of CYP3A was enhanced about twofold by this treatment. 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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Miyauchi Y,Tanaka Y,Nagata K,Yamazoe Y,Mackenzie PI,Yamada H,Ishii Y

doi

10.1111/bph.14900

subject

Has Abstract

pub_date

2020-03-01 00:00:00

pages

1077-1089

issue

5

eissn

0007-1188

issn

1476-5381

journal_volume

177

pub_type

杂志文章

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