Zhu Qin-shi, Xing Wenxue, Qian Bin, von Dippe Patricia, Shneider Benjamin L, Fox Victor L, Levy Daniel
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
Biochim Biophys Acta. 2003 Jul 30;1638(3):208-16. doi: 10.1016/s0925-4439(03)00085-1.
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.
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，并且还能够介导胆汁酸依赖于钠的方式摄取进入肝细胞。研究发现一名受试者（S-1），在没有明显肝细胞损伤的情况下血清胆汁盐水平极高，提示胆汁酸摄取存在缺陷。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）存在一个点突变，这导致在瞬时转染实验中EPHX1启动子活性显著降低。使用来自每个区域的放射性标记寡核苷酸进行凝胶迁移实验，得到了特定的转录因子结合模式，在存在突变的情况下这些模式发生了改变。这些研究表明，在高胆血症患者中mEH的表达大大降低，提示mEH参与人肝脏中依赖于钠的胆汁酸摄取，其缺失可能导致该疾病的病因。
