期刊
JOURNAL OF PHARMACOLOGICAL SCIENCES
卷 130, 期 2, 页码 66-71出版社
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1016/j.jphs.2015.11.006
关键词
Pregnane X receptor; SUMOylation; Transcriptional activity; CYP3A4; P-gp
资金
- National Natural Science Foundation of China [81402998]
- Natural Science Foundation of Guangdong Province [2015A030313059]
- Major Scientific and Technological Project of Guangdong Province [2011A080300001, 2012A080202013]
- Medical Scientific Research Foundation of Guangdong Province, China [B2014124]
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. (C) 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V.
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