Putative Role of the Orphan Nuclear Receptor SXR (Steroid and Xenobiotic Receptor) in the Mechanism of CYP3A4 Inhibition by Xenobiotics*
Putative Role of the Orphan Nuclear Receptor SXR (Steroid and Xenobiotic Receptor) in the Mechanism of CYP3A4 Inhibition by Xenobiotics*
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DOI：
10.1074/jbc.m111245200
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发表时间：
2002-09
期刊：
影响因子：
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通讯作者：
A. Takeshita;M. Taguchi;N. Koibuchi;Y. Ozawa
中科院分区：
文献类型：
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作者：
A. Takeshita;M. Taguchi;N. Koibuchi;Y. Ozawa
细胞色素P450单加氧酶3A4(细胞色素P450单加氧酶3A4)负责内源性类固醇和药物在肝脏的代谢。许多人CYP3A4的诱导剂，如利福平，作为配体与孤儿核受体SXR(类固醇和异生受体)结合，刺激位于CYP3A4启动子的异生反应元件上的转录。相反，目前还不知道SXR是否介导了转录抑制。因此，我们在没有配体和存在配体的情况下，使用报告分析方法研究了SXR的转录抑制及其与辅阻遏物NCoR(核受体辅阻遏子)和SMRT(维甲酸和甲状腺受体沉默介导物)的相互作用。在HepG2细胞中，SMRT-SXR通过特异性的SMRT-SXR相互作用，不仅能抑制基础转录活性，而且还能抑制利福平诱导的细胞色素P3A4启动子上SXR的转录活性。有趣的是，利福平还增加了SXR与SMRT以及与辅助激活剂SRC-1的相互作用。另一方面，抗真菌药酮康唑减少了SXR与SRC-1和SMRT的相互作用。酮康唑部分抑制皮质酮诱导的细胞色素P3A4启动子上SXR介导的转录。综上所述，我们的结果表明，不同外源生物诱导的辅激活子和辅抑制子之间的差异相互作用可能会改变SXR介导的转录。此外，酮康唑对CYP3A4基因抑制的作用可能在一定程度上解释了药物在转录水平上抑制CYP3A4的作用。
Cytochrome P450 monooxygenase 3A4 (CYP3A4) is responsible for the metabolism of endogenous steroids and drugs in liver. Many inducers of human CYP3A4, such as rifampicin, bind to the orphan nuclear receptor SXR (steroid and xenobiotic receptor) as ligands and stimulate transcription on xenobiotic response elements located in the CYP3A4 promoter. Conversely, it is not known whether SXR mediates the transcriptional repression. We thus examined transcriptional repression of SXR and its interaction with corepressors, NCoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid receptors) using reporter assays in the absence and presence of ligand. Cotransfection of SMRT, but not NCoR, inhibited not only basal but also rifampicin-induced transcriptional activity of SXR on the CYP3A4 promoter through specific SMRT-SXR interaction in HepG2 cells. Interestingly, rifampicin also increased the interaction of SXR with SMRT as well as with coactivator SRC-1. On the other hand, the anti-fungal agent ketoconazole decreased SXR interaction with both SRC-1 and SMRT. Ketoconazole partially inhibited corticosterone-induced SXR-mediated transcription on the CYP3A4 promoter. Taken together, our results suggest that the differential interaction of coactivators and corepressors induced by various xenobiotics may alter SXR-mediated transcription. Further, the effects of ketoconazole on theCYP3A4 gene suppression may explain, in part, drug-induced inhibition of the CYP3A4 action at the transcriptional level.