Polycyclic Aromatic Hydrocarbons Activate CYP3A4 Gene Transcription through Human Pregnane X Receptor
Polycyclic Aromatic Hydrocarbons Activate CYP3A4 Gene Transcription through Human Pregnane X Receptor
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DOI：
10.2133/dmpk.dmpk-11-rg-094
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发表时间：
2012-04-25
影响因子：
2.1
通讯作者：
Nagata, Kiyoshi
中科院分区：
文献类型：
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作者：
Kumagai, Takeshi;Suzuki, Hiroyuki;Nagata, Kiyoshi
芳香烃受体（AhR）激活剂已被证明诱导细胞色素P450（P450）1家族的成员。在这里，我们证明了AhR激活剂通过人胆甾烷X受体（PXR）诱导CYP 3A 4。AhR激活剂多环芳烃（PAHs）和2，3，7，8-四氯二苯并对二恶英（TCDD）可增加HepG 2细胞CYP 3A 4报告基因活性和mRNA表达。用香烟焦油处理也增加了CYP 3A 4报告活性。通过引入人PXR-小干扰RNA，而不是通过人AhR-小干扰RNA，CYP 3A 4报告基因活性的增加被明显敲低。CYP 3A 4报告活性增强过表达的人PXR进一步增加治疗与多环芳烃和TCDD以及利福平治疗。这些结果表明，香烟烟雾中所含的多环芳烃诱导人肝脏CYP 3A 4。
Aryl hydrocarbon receptor (AhR) activators have been shown to induce members of the cytochrome P450 (P450) 1 family. Here we demonstrate that the AhR activators induce CYP3A4 through human pregnane X receptor (PXR). AhR activators, polycyclic aromatic hydrocarbons (PAHs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased CYP3A4 reporter activity and CYP3A4 mRNA expression in HepG2 cells. The CYP3A4 reporter activity was also increased by treatment with cigarette tar. The increased CYP3A4 reporter activity was clearly knocked down by the introduction of human PXR-small interfering RNA, but not by that of human AhR-small interfering RNA. The CYP3A4 reporter activity enhanced by overexpression of human PXR was further increased by treatment with PAHs and TCDD as well as by treatment with rifampicin. These results suggest that PAHs contained in cigarette smoke induce CYP3A4 in human liver.