RRC ID 59836
Author Okamura M, Shizu R, Hosaka T, Sasaki T, Yoshinari K.
Title Possible involvement of the competition for the transcriptional coactivator glucocorticoid receptor-interacting protein 1 in the inflammatory signal-dependent suppression of PXR-mediated CYP3A induction in vitro.
Journal Drug Metab Pharmacokinet
Abstract Pregnane X receptor (PXR) is a xenobiotic-responsive transcription factor that plays a pivotal role in drug metabolism and disposition in livers and intestines through regulating the expression of drug metabolizing enzymes and transporters. It is well known that PXR-mediated induction of CYP3A enzymes is downregulated under inflammatory conditions. Although some reports suggest that the downregulation is caused by an inhibition of transcriptional activity of PXR by nuclear factor-κB (NF-κB), a key inflammation-associated transcription factor, the detailed mechanism remains unclear. In reporter assays using the CYP3A4 promoter, the PXR-mediated transcription was suppressed by inflammatory stimuli and co-expression of NF-κB or activator protein-1 (AP-1), suggesting that not only NF-κB but also AP-1 play a key role in the suppression of CYP3A induction. We also revealed that PXR, NF-κB and AP-1 commonly use the coactivator glucocorticoid receptor-interacting protein 1 (GRIP1) for their transcriptional activation and that inflammatory stimuli inhibited the GRIP1-mediated enhancement of the transcription by PXR. These results suggest that under inflammatory conditions activated NF-κB and/or AP-1 compete with PXR for GRIP1 usage to reduce the PXR/GRIP1-mediated transcription of CYP3A genes.
Volume 34(4)
Pages 272-279
Published 2019-8
DOI 10.1016/j.dmpk.2019.04.005
PII S1347-4367(19)30018-7
PMID 31280915
MeSH Cells, Cultured Cytochrome P-450 CYP3A / genetics Cytochrome P-450 CYP3A / metabolism* HEK293 Cells Hep G2 Cells Humans Inflammation / metabolism* NF-kappa B / metabolism Nuclear Receptor Coactivator 2 / metabolism* Pregnane X Receptor / metabolism* Signal Transduction*
IF 1.874
Times Cited 1
Human and Animal Cells 293T(RCB2202), Hep G2(RCB1886)