CYP3A4*1G regulates CYP3A4 intron 10 enhancer and promoter activity in an allelic-dependent manner.
CYP3A4*1G regulates CYP3A4 intron 10 enhancer and promoter activity in an allelic-dependent manner.
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DOI：
10.5414/cp202272
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发表时间：
2015-08
影响因子：
0.8
通讯作者：
Weihong Yang;Dengzhi Zhao;Shengnan Han;Zengyuan Tian;Liang Yan;Guoqiang Zhao;Q. Kan;Wei Zhang;Lirong Zhang
中科院分区：
文献类型：
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作者：
Weihong Yang;Dengzhi Zhao;Shengnan Han;Zengyuan Tian;Liang Yan;Guoqiang Zhao;Q. Kan;Wei Zhang;Lirong Zhang
目的人CYP 3A 4内含子10中的CYP 3A 4 *1G（G > A）与CYP 3A 4代谢药物的疗效有关。本研究的目的是预测其在CYP 3A 4表达调控中的作用。方法应用生物信息学方法和增强子或启动子报告基因分析技术对HepG 2细胞中CYP 3A 4 *1G等位基因进行功能分析。结果CYP 3A 4基因内含子10中存在CAATboxes、TATA-boxes、Sp1、SMARCA3.01和BoxII-like序列等转录调控元件。SMARCA 3.01和Box II样序列负责CYP 3A 4 *1G等位基因上转录因子的差异结合。在CYP 3A 4 *1G中，G等位基因以位置依赖和方向依赖的方式增强CYP 3A 4启动子的表达，而A等位基因以位置非依赖和方向非依赖的方式增强CYP 3A 4启动子的表达。此外，G等位基因和A等位基因都表现出较强的转录激活，但后者的启动子活性高于前者。此外，A等位基因表现出比CYP 3A 4启动子更大的活性。结论CYP 3A 4 *1G基因对CYP 3A 4内含子10增强子和启动子活性的调控具有等位基因依赖性。
OBJECTIVE CYP3A4*1G (G > A) in human CYP3A4 intron 10 is associated with therapeutic effects of CYP3A4-metabolized drugs. The aim of this study was to predict its function in the regulation of CYP3A4 expression. METHODS Functional analysis of the CYP3A4*1G allele was performed using bioinformatic methods and enhancer or promoter reporter assays in HepG2 cells. RESULTS Transcription regulatory elements like CAATboxes, TATA-boxes, Sp1, SMARCA3.01, and Box II-like sequence were present in the intron 10 of CYP3A4. SMARCA3.01 and Box II-like sequence were responsible for differential binding of transcription factors on the CYP3A4*1G allele. In CYP3A4*1G, the G allele enhanced expression of the CYP3A4 promoter in a position-dependent and orientation-dependent manner, however, the A allele enhanced expression of the CYP3A4 promoter in a position-independent and orientation-independent manner. In addition, the G allele and the A allele both displayed strong transcriptional activation, but the latter showed higher promoter activity than the former. Also, the A allele showed greater activity than the CYP3A4 promoter. CONCLUSION These results in vitro suggest that CYP3A4*1G regulates CYP3A4 intron 10 enhancer and promoter activity in an allelic-dependent manner.