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.

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. Drug Metab Pharmacokinet. 2019 Apr 19;: Authors: Okamura M, Shizu R, Hosaka T, Sasaki T, Yoshinari K 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. The...
Source: Drug Metabolism and Pharmacokinetics - Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research