Structural organization and characterization of the regulatory element of the human carboxylesterase (CES1A1 and CES1A2) genes
Structural organization and characterization of the regulatory element of the human carboxylesterase (CES1A1 and CES1A2) genes
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DOI：
10.2133/dmpk.23.73
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发表时间：
2008-01-01
影响因子：
2.1
通讯作者：
Chiba, Kan
中科院分区：
文献类型：
--
作者：
Hosokawa, Masakiyo;Furihata, Tomomi;Chiba, Kan
哺乳动物羧酸酯酶包括多基因家族，其基因产物定位于内质网中。羧酸酯酶催化各种外源性物质和内源性底物如酯键、酰胺键和硫酯键的水解，并且被认为主要在药物代谢中起作用。我们提出了人肝羧酸酯酶活性的个体差异导致CES 1A同工酶表达水平差异的可能性。然而，很少有人知道人类羧酸酯酶基因的转录调控。在本研究中，我们分离了两个编码人羧酸酯酶CES 1A的CES基因，分别命名为CES 1A 1（AB 119997）和CES 1A 2（AB 119998）。除了外显子1和5'调控元件外，这些基因是相同的。我们研究了这两个CES基因的转录调控。报告基因分析和电泳迁移率变动分析表明，Sp1和C/EBP α可以结合到CES 1A 1启动子的每个响应元件，但Sp1和C/EBP不能结合到CES 1A 2启动子的响应元件。因此，肝和肺中的CES 1A 1 mRNA表达水平远高于CES 1A 2 mRNA的表达水平。认为这些结果提供了人类羧酸酯酶同工酶个体差异的信息。
Mammalian carboxylesterases comprise a multigene family, the gene products of which are localized in the endoplasmic reticulum. The carboxylesterases catalyze the hydrolysis of various xenobiotics and endogenous substrates such as ester, amide and thioester bonds and are thought to function mainly in drug metabolism. We have suggested the possibility that individual variation of human liver carboxylesterase activity causes the difference in expression levels of CES1A isozymes. However, little is known about the transcriptional regulation of human carboxylesterase genes. In the present study, we isolated two CES genes encoding human carboxylesterase CES1A, which were designated as CES1A1 (AB119997) and CES1A2 (AB119998). These genes were identical except for exon 1 and the 5' regulatory element. We investigated the transcriptional regulation of these two CES genes. A reporter gene assay and electrophoretic mobility shift assay demonstrated that Sp1 and C/EBP alpha could bind to each responsive element of the CES1A1 promoter but that the Sp1 and C/EBP could not bind to the responsive element of the CES1A2 promoter. Thus, CES1A1 mRNA expression level is much higher than the expression level of CES1A2 mRNA in the liver and lung. It is thought that these results provide information on individual variation of human carboxylesterase isozymes.