@article {Yanmol.117.108225, author = {Liang Yan and Yiting Wang and Jingyang Liu and Yali Nie and Xiaobo Zhong and Quancheng Kan and Lirong Zhang}, title = {Alterations of Histone Modifications Contribute to Pregnane X Receptor-mediated Induction of CYP3A4 by Rifampicin}, elocation-id = {mol.117.108225}, year = {2017}, doi = {10.1124/mol.117.108225}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Cytochrome P450 3A4 (CYP3A4) is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60\% of the clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modifications in rifampicin-induced expression of CYP3A4 in LS174T cells. We found that the induction of CYP3A4 mRNA by rifampicin in LS174T cells was associated with increased levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3 acetylation and a decreased level of histone H3 lysine 27 trimethylation (H3K27me3) in the CYP3A4 promoter. Rifampicin enhanced the recruitment of nuclear receptor coactivator 6 (NCOA6) and histone acetyltransferase p300 (p300) to the CYP3A4 promoter. Silencing NCOA6 or p300 by shRNAs resulted in inhibition of the CYP3A4 induction as well as the altered levels of H3K4me3, H3K27me3, or H3 acetylation in the CYP3A4 promoter, respectively. Knockdown of pregnane X receptor (PXR) expression not only diminished the recruitment of NCOA6 and p300, but also abolished the changes of H3K4me3, H3K27me3, and H3 acetylation levels in the CYP3A4 promoter caused by rifampicin. Moreover, rifampicin treatment enhanced the nuclear accumulation and interactions between PXR and NCOA6/p300. In conclusion, we show that the alterations of histone modifications contribute to the PXR-mediated induction of CYP3A4 by rifampicin.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2017/05/25/mol.117.108225}, eprint = {https://molpharm.aspetjournals.org/content/early/2017/05/25/mol.117.108225.full.pdf}, journal = {Molecular Pharmacology} }