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首页> 外文期刊>Journal of biochemical and molecular toxicology >Constitutive activation of nuclear factor-E2-related factor 2 induces biotransformation enzyme and transporter expression in livers of mice with hepatocyte-specific deletion of Kelch-like ECH-associated protein 1.
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Constitutive activation of nuclear factor-E2-related factor 2 induces biotransformation enzyme and transporter expression in livers of mice with hepatocyte-specific deletion of Kelch-like ECH-associated protein 1.

机译:组成性激活核因子E2相关因子2诱导肝细胞特异性缺失Kelch样ECH相关蛋白1的小鼠肝脏中的生物转化酶和转运蛋白表达。

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摘要

Chemicals that activate nuclear factor-E2-related factor 2 (Nrf2) often increase multidrug-resistance-associated protein (Mrp) expression in liver. Hepatocyte-specific deletion of Kelch-like ECH-associated protein 1 (Keap1) activates Nrf2. Use of hepatocyte-specific Keap1 deletion represents a nonpharmacological method to determine whether constitutive Nrf2 activation upregulates liver transporter expression in vivo. The mRNA, protein expression, and localization of several biotransformation and transporters were determined in livers of wild-type and hepatocyte-specific Keap1-null mice. Sulfotransferase 2a1/2, NADP(H):quinone oxidoreductase 1, cytochrome P450 2b10, 3a11, and glutamate-cysteine ligase catalytic subunit expression were increased in livers of Keap1-null mice. Organic anion-transporting polypeptide 1a1 expression was nearly abolished, as compared to that detected in livers of wild-type mice. By contrast, Mrp 1-5 mRNA and protein levels were increased in Keap1-null mouse livers, with Mrp4 expression being more than 15-fold higher than wild types. In summary, Nrf2 has a significant role in affecting Oatp and Mrp expressions.
机译:激活核因子E2相关因子2(Nrf2)的化学物质通常会增加肝脏中与多药耐药相关的蛋白质(Mrp)的表达。肝细胞特异性的Kelch样ECH相关蛋白1(Keap1)的删除激活Nrf2。肝细胞特异的Keap1缺失的使用代表了一种非药理学方法,用于确定本构性Nrf2激活是否在体内调节肝转运蛋白的表达。在野生型和肝细胞特异性的Keap1-null小鼠的肝脏中确定了mRNA,蛋白质表达以及几种生物转化和转运蛋白的定位。在Keap1无效的小鼠肝脏中,磺基转移酶2a1 / 2,NADP(H):醌氧化还原酶1,细胞色素P450 2b10、3a11和谷氨酸半胱氨酸连接酶催化亚基的表达增加。与野生型小鼠肝脏中检测到的相比,有机阴离子运输多肽1a1的表达几乎被废除了。相比之下,Keap1基因缺失的小鼠肝脏中Mrp 1-5 mRNA和蛋白水平增加,Mrp4表达比野生型高15倍以上。总之,Nrf2在影响Oatp和Mrp的表达中具有重要作用。

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