Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia
Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia
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DOI：
10.1016/s0925-4439(03)00085-1
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发表时间：
2003-07-30
影响因子：
6.2
通讯作者：
Levy, D
中科院分区：
文献类型：
--
作者：
Zhu, QS;Xing, WX;Levy, D
微粒体环氧化物水解酶（mEH）是一种双功能蛋白，在致癌物代谢中起核心作用，也能够介导胆汁酸进入肝细胞的钠依赖性摄取。研究已经确定了一个受试者（S-1），在没有观察到的肝细胞损伤的情况下，血清胆盐水平极高，提示胆汁酸摄取缺陷。在该个体中，mEH蛋白和mEH mRNA水平分别降低了约95%和85%，而另一种胆汁酸转运蛋白（NTCP）的表达和氨基酸序列未受影响。mEH基因（EPHX1）的序列分析显示，在上游HNF-3位点（等位基因I）和内含子1（等位基因II）发生点突变，导致EPHX1启动子活性在瞬时转染试验中显著降低。使用来自每个区域的放射性标记寡核苷酸的凝胶移位分析导致特定的转录因子结合模式，这些模式在突变的存在下被改变。这些研究表明，mEH在高胆酸血症患者中的表达大大降低，提示mEH参与人肝脏钠依赖性胆汁酸摄取，其缺失可能与该病的病因有关。(C) 2003 Elsevier Science B.V.版权所有
Microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a central role in carcinogen metabolism and is also able to mediate the sodium-dependent uptake of bile acids into hepatocytes. Studies have identified a subject (S-1) with extremely elevated serum bile salt levels in the absence of observable hepatocellular injury, suggesting a defect in bile acid uptake. In this individual, mEH protein and mEH mRNA levels were reduced by approximately 95% and 85%, respectively, whereas the expression and amino acid sequence of another bile acid transport protein (NTCP) was unaffected. Sequence analysis of the mEH gene (EPHX1) revealed a point mutation at an upstream HNF-3 site (allele I) and in intron 1 (allele II), which resulted in a significant decrease in EPHX1 promoter activity in transient transfection assays. Gel shift assays using a radiolabeled oligonucleotide from each region resulted in specific transcription factor binding patterns, which were altered in the presence of the mutation. These studies demonstrate that the expression of mEH is greatly reduced in a patient with hypercholanemia, suggesting that mEH participates in sodium-dependent bile acid uptake in human liver where its absence may contribute to the etiology of this disease. (C) 2003 Elsevier Science B.V. All rights reserved.