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SUMOylation of pregnane X receptor suppresses rifampicin-induced CYP3A4 and P-gp expression and activity in LS174T cells

SUMOylation of pregnane X receptor suppresses rifampicin-induced CYP3A4 and P-gp expression and activity in LS174T cells

Authors :
Huasen Tan
Chenshu Xu
Hang Zeng
Ying Wang
Yingmei Li
Xiaomei Fan
Pan Chen
Yiming Jiang
Xiao Chen
Min Huang
Huichang Bi
Source :
Journal of Pharmacological Sciences, Vol 130, Iss 2, Pp 66-71 (2016)
Publication Year :
2016
Publisher :
Elsevier, 2016.

Abstract

The pregnane X receptor (PXR) has been well-established as a critical mediator in regulating important drug metabolizing enzymes and transporter proteins, including cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Previous studies identified that PXR served as a molecular target of SUMOylation. However, the impact of SUMOylation of PXR on its transcriptional activity in regulating the expression/activity of the target genes is poorly investigated. In the current study, we established cell-based models of SUMOylated PXR in LS174T cells to investigate the impact of SUMOylation of PXR on regulating the expression/activity of CYP3A4 and P-gp. Our results revealed that rifampicin-induced PXR transactivation of the CYP3A4 and P-gp promoter was suppressed by SUMOylation of PXR in reporter gene assay. The mRNA and protein expression of CYP3A4 and P-gp was also suppressed. Moreover, CYP3A4 enzymatic assay and Rho123 intracellular assay revealed that rifampicin-induced CYP3A4 and P-gp activity was also suppressed by SUMOylated PXR. Our data collectively indicated for the first time that SUMOylation of PXR exerts suppressive effect on rifampicin-induced expression and activity of CYP3A4 and P-gp, which suggest that alteration in the SUMOylation status of PXR will be expected to affect the CYP3A4 mediated drug metabolism and P-gp mediated drug transport.

Details

Language :
English
ISSN :
13478613
Volume :
130
Issue :
2
Database :
Directory of Open Access Journals
Journal :
Journal of Pharmacological Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.2acfb0aab0db439f8187e063a8372754
Document Type :
article
Full Text :
https://doi.org/10.1016/j.jphs.2015.11.006