Increased Nrf2 Activation in Livers from Keap1-Knockdown Mice Increases Expression of Cytoprotective Genes that Detoxify Electrophiles more than those that Detoxify Reactive Oxygen Species
Increased Nrf2 Activation in Livers from Keap1-Knockdown Mice Increases Expression of Cytoprotective Genes that Detoxify Electrophiles more than those that Detoxify Reactive Oxygen Species
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DOI：
10.1093/toxsci/kfn267
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发表时间：
2009-03-01
影响因子：
3.8
通讯作者：
Klaassen, Curtis D.
中科院分区：
文献类型：
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作者：
Reisman, Scott A.;Yeager, Ronnie L.;Klaassen, Curtis D.
核因子红细胞2相关因子2（Nrf 2）是一种对亲电和氧化应激保护至关重要的转录因子。在最近敲低kelch样ECH相关蛋白1（Keap 1-kd小鼠）（Nrf 2的胞质阻遏物）的工程小鼠中，肝脏中Keap 1 mRNA减少55%，Nrf 2蛋白增加200%。用Nrf 2缺失小鼠进行的实验已经证明了缺乏Nrf 2的影响。然而，人们对更多Nrf 2激活的生物学效应知之甚少。因此，Keap 1-kd小鼠的肝脏表型以及细胞保护基因的肝脏mRNA表达在野生型、Nrf 2-null和Keap 1-kd小鼠之间进行了比较。在野生型、Nrf 2-null和Keap 1-kd小鼠中确定了三种不同的肝脏基因表达模式。第一种模式包括Nrf 2基因缺失小鼠中较低的基因和Keap 1-kd小鼠中比野生型小鼠高得多的基因，其中包括主要负责亲电体解毒和消除的基因，如NAD（P）H：醌氧化还原酶1和谷胱甘肽-S-转移酶（Gst），以及多药耐药相关蛋白。第二种模式包括在Nrf 2缺失小鼠中较低但在Keap 1-kd小鼠中不增加的基因，包括环氧化物水解酶-1、UDP-葡萄糖醛酸转移酶、醛脱氢酶等基因，以及在活性氧解毒中重要的基因，如超氧化物歧化酶1和2、过氧化氢酶和过氧化物氧还蛋白1。第三种模式包括野生型，Nrf 2-null和Keap 1-kd小鼠之间没有差异的基因，包括谷胱甘肽过氧化物酶，微粒体GST和摄取转运蛋白等基因。总之，本研究表明，肝Nrf 2的激活增加是更重要的解毒和消除亲电体比活性氧。
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor critical for protection against electrophilic and oxidative stress. In a recently engineered mouse with knockdown of kelch-like ECH associated protein 1 (Keap1-kd mice), the cytosolic repressor of Nrf2, there is a 55% decrease in Keap1 mRNA and a 200% increase in Nrf2 protein in liver. Experiments with Nrf2-null mice have demonstrated the effects of a lack of Nrf2. However, little is known about the biological effects of more Nrf2 activation. Accordingly, the hepatic phenotype of Keap1-kd mice, as well as the hepatic mRNA expression of cytoprotective genes were compared among wild-type, Nrf2-null, and Keap1-kd mice. Three distinct patterns of hepatic gene expression were identified among wild-type, Nrf2-null, and Keap1-kd mice. The first pattern encompassed genes that were lower in Nrf2-null mice and considerably higher in Keap1-kd mice than wild-type mice, which included genes mainly responsible for the detoxification and elimination of electrophiles, such as NAD(P)H:quinone oxidoreductase 1 and glutathione-S-transferases (Gst), and multidrug resistance-associated proteins. The second pattern encompassed genes that were lower in Nrf2-null mice but not increased in Keap1-kd mice, and included genes, such as epoxide hydrolase-1, UDP-glucuronosyltransferases, aldehyde dehydrogenases, as well as genes important in the detoxification of reactive oxygen species, such as superoxide dismutase 1 and 2, catalase, and peroxiredoxin 1. The third pattern encompassed genes that were not different among wild-type, Nrf2-null, and Keap1-kd mice and included genes such as glutathione peroxidase, microsomal Gsts, and uptake transporters. In conclusion, the present study suggests that increased activation of hepatic Nrf2 is more important for the detoxification and elimination of electrophiles than reactive oxygen species.