RRC ID |
59836
|
著者 |
Okamura M, Shizu R, Hosaka T, Sasaki T, Yoshinari K.
|
タイトル |
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.
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ジャーナル |
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.
|
巻・号 |
34(4)
|
ページ |
272-279
|
公開日 |
2019-8-1
|
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
|
引用数 |
1
|
リソース情報 |
ヒト・動物細胞 |
293T(RCB2202)
Hep G2(RCB1886) |