Yamasaki Yuki, Kobayashi Kaoru, Inaba Asumi, Uehara Daisuke, Tojima Hiroki, Kakizaki Satoru, Chiba Kan
a Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University , Chiba , Japan and.
b Division of Gastroenterology and Hepatology, Department of Internal Medicine, Graduate School of Medicine, Gunma University , Maebashi , Japan.
Xenobiotica. 2018 Nov;48(11):1098-1105. doi: 10.1080/00498254.2017.1400128. Epub 2017 Nov 23.
Rifampicin (RIF), a typical ligand of human pregnane X receptor (PXR), powerfully induces the expression of cytochrome P450 3A4 (CYP3A4) in humans. Although it is thought that RIF is not a ligand of rodent PXR, treatment with high-dose RIF (e.g. more than 20 mg/kg) increases the expression of CYP3A in the mouse liver. In this study, we investigated whether the induction of CYP3A by high-dose RIF in the mouse liver is mediated via indirect activation of mouse PXR (mPXR). The results showed that high-dose RIF increased the expression of CYP3A11 and other PXR-target genes in the liver of wild-type mice but not PXR-knockout mice. However, the results of reporter gene and ligand-dependent assembly assays showed that RIF does not activate mPXR in a ligand-dependent manner. In addition, high-dose RIF stimulated nuclear accumulation of mPXR in the mouse liver, and geldanamycin and okadaic acid attenuated the induction of Cyp3a11 and other PXR-target genes in primary hepatocytes, suggesting that high-dose RIF triggers nuclear translocation of mPXR. In conclusion, the present study suggests that high-dose RIF stimulates nuclear translocation of mPXR in the liver of mice by indirect activation, resulting in the transactivation of Cyp3a11 and other PXR-target genes.
利福平（RIF）是人类孕烷X受体（PXR）的典型配体，可强力诱导人类细胞色素P450 3A4（CYP3A4）的表达。尽管人们认为RIF不是啮齿动物PXR的配体，但用高剂量RIF（例如超过20mg/kg）处理会增加小鼠肝脏中CYP3A的表达。在本研究中，我们调查了高剂量RIF在小鼠肝脏中对CYP3A的诱导是否通过小鼠PXR（mPXR）的间接激活介导。结果显示，高剂量RIF增加了野生型小鼠肝脏中CYP3A11和其他PXR靶基因的表达，但对PXR基因敲除小鼠则无此作用。然而，报告基因和配体依赖性组装试验的结果表明，RIF不会以配体依赖性方式激活mPXR。此外，高剂量RIF刺激了小鼠肝脏中mPXR的核积累，格尔德霉素和冈田酸减弱了原代肝细胞中Cyp3a11和其他PXR靶基因的诱导，表明高剂量RIF触发了mPXR的核转位。总之，本研究表明，高剂量RIF通过间接激活刺激小鼠肝脏中mPXR的核转位，导致Cyp3a11和其他PXR靶基因的反式激活。
