Alterations of Histone Modifications Contribute to Pregnane X Receptor-Mediated Induction of CYP3A4 by Rifampicin
Alterations of Histone Modifications Contribute to Pregnane X Receptor-Mediated Induction of CYP3A4 by Rifampicin
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DOI：
10.1124/mol.117.108225
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发表时间：
2017-05
影响因子：
3.6
通讯作者：
Liang Yan;Yiting Wang;Jingyang Liu;Ya-li Nie;Xiao-bo Zhong;Q. Kan;Lirong Zhang
中科院分区：
文献类型：
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作者：
Liang Yan;Yiting Wang;Jingyang Liu;Ya-li Nie;Xiao-bo Zhong;Q. Kan;Lirong Zhang
CYP 3A 4是人体内主要的药物代谢酶之一，负责60%的临床药物的代谢。许多药物能够诱导CYP 3A 4的表达，这通常会引起药物相互作用和药物不良反应。本研究旨在探讨组蛋白修饰在利福平诱导LS 174 T细胞CYP 3A 4表达中的作用。我们发现，利福平在LS 174 T细胞中对CYP 3A 4 mRNA的诱导（4- 15倍）与CYP 3A 4启动子中组蛋白H3赖氨酸4三甲基化（H3 K4 me 3，高于1.8倍）和H3乙酰化（高于2倍）水平的增加以及组蛋白H3赖氨酸27三甲基化（H3 K27 me 3，约50%）水平的降低相关。利福平增强了细胞核受体辅激活因子6（NCOA 6，3倍以上）和组蛋白乙酰转移酶p300（p300，1.6倍以上）向CYP 3A 4启动子的募集。通过短发夹RNA沉默NCOA 6或p300导致CYP 3A 4诱导的抑制以及CYP 3A 4启动子中H3 K4 me 3、H3 K27 me 3或H3乙酰化水平的改变。敲低CYP 3A 4受体（PXR）的表达不仅抑制了NCOA 6和p300的募集，而且消除了利福平引起的CYP 3A 4启动子中H3 K4 me 3、H3 K27 me 3和H3乙酰化水平的变化。此外，利福平处理增强了PXR和NCOA 6/p300之间的核积聚和相互作用。总之，我们发现组蛋白修饰的改变有助于利福平对PXR介导的CYP 3A 4的诱导。
CYP3A4 is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of 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 (4- to 15-fold) by rifampicin in LS174T cells was associated with increased levels of histone H3 lysine 4 trimethylation (H3K4me3, above 1.8-fold) and H3 acetylation (above 2-fold) and a decreased level of histone H3 lysine 27 trimethylation (H3K27me3, about 50%) in the CYP3A4 promoter. Rifampicin enhanced recruitment to the CYP3A4 promoter of nuclear receptor coactivator 6 (NCOA6, above 3-fold) and histone acetyltransferase p300 (p300, above 1.6-fold). Silencing NCOA6 or p300 by short-hairpin RNAs resulted in inhibition of the CYP3A4 induction as well as altered levels of H3K4me3, H3K27me3, or H3 acetylation in the CYP3A4 promoter. Knockdown of pregnane X receptor (PXR) expression not only suppressed the recruitment of NCOA6 and p300 but also abolished the changes caused by rifampicin in H3K4me3, H3K27me3, and H3 acetylation levels in the CYP3A4 promoter. 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.