CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes.
CDDO-Im protects from acetaminophen hepatotoxicity through induction of Nrf2-dependent genes.
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DOI：
10.1016/j.taap.2008.12.024
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发表时间：
2009-04-01
影响因子：
3.8
通讯作者：
Klaassen CD
中科院分区：
文献类型：
--
作者：
Reisman SA;Buckley DB;Tanaka Y;Klaassen CD
CDDO-Im是一种合成的三萜类化合物，最近显示通过Nrf 2-Keap 1途径诱导细胞保护基因，Nrf 2-Keap 1途径是诱导细胞保护基因响应氧化应激的重要机制。在氧化或亲电损伤后，转录因子Nrf 2易位到细胞核，与小Maf蛋白异二聚化，并结合到各种细胞保护基因上游启动子区的抗氧化反应元件（战神）。为了进一步阐明CDDO-Im的肝保护作用，将野生型和Nrf 2缺失小鼠用CDDO-Im（lmg/kg，i. p.）或媒介物（DMSO），然后施用对乙酰氨基酚（500 mg/kg，i. p.）。用CDDO-Im预处理野生型小鼠减少了对乙酰氨基酚引起的肝损伤。相反，在Nrf 2缺失小鼠中未观察到CDDO-Im的肝保护作用。CDDO-Im增加野生型小鼠中Nrf 2蛋白表达和Nrf 2-ARE结合，但不增加Nrf 2-null小鼠。此外，CDDO-Im以剂量和时间依赖性方式增加Nrf 2靶基因NAD（P）H：醌氧化还原酶-1（Nqo 1）、谷氨酸-半胱氨酸连接酶催化亚基（Gclc）和血红素加氧酶-1（Ho-1）的mRNA表达。相反，CDDO-Im在Nrf 2缺失小鼠中不诱导Nqo 1、Gclc和Ho-1 mRNA表达。总的来说，本研究表明，CDDO-Im预处理诱导Nrf 2依赖性细胞保护基因，并保护肝脏免受对乙酰氨基酚诱导的肝损伤。
CDDO-Im is a synthetic triterpenoid recently shown to induce cytoprotective genes through the Nrf2-Keap1 pathway, an important mechanism for the induction of cytoprotective genes in response to oxidative stress. Upon oxidative or electrophilic insult, the transcription factor Nrf2 translocates to the nucleus, heterodimerizes with small Maf proteins, and binds to antioxidant response elements (AREs) in the upstream promoter regions of various cytoprotective genes. To further elucidate the hepatoprotective effects of CDDO-Im, wild-type and Nrf2-null mice were pretreated with CDDO-Im (1 mg/kg, i.p.) or vehicle (DMSO), and then administered acetaminophen (500 mg/kg, i.p.). Pretreatment of wild-type mice with CDDO-Im reduced liver injury caused by acetaminophen. In contrast, hepatoprotection by CDDO-Im was not observed in Nrf2-null mice. CDDO-Im increased Nrf2 protein expression and Nrf2-ARE binding in wild-type, but not Nrf2–null mice. Furthermore, CDDO-Im increased the mRNA expression of the Nrf2 target genes NAD(P)H: quinone oxidoreductase-1 (Nqo1); glutamate-cysteine ligase, catalytic subunit (Gclc); and heme-oxygenase-1 (Ho-1), in both a dose- and time-dependent manner. Conversely, CDDO-Im did not induce Nqo1, Gclc, and Ho-1 mRNA expression in Nrf2-null mice. Collectively, the present study shows that CDDO-Im pretreatment induces Nrf2-dependent cytoprotective genes and protects the liver from acetaminophen-induced hepatic injury.
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影响因子：
2.7
作者：
Honda, T;Rounds, BV;Sporn, MB
通讯作者：
Sporn, MB
影响因子：
4.5
作者：
Moffit, Jeffrey S.;Aleksunes, Lauren M.;Manautou, Jose E.
通讯作者：
Manautou, Jose E.
影响因子：
3.8
作者：
Knight, TR;Kurtz, A;Jaeschke, H
通讯作者：
Jaeschke, H
DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
Itoh, K;Chiba, T;Nabeshima, Y
通讯作者：
Nabeshima, Y
影响因子：
11.2
作者：
Liby, K;Hock, T;Sporn, MB
通讯作者：
Sporn, MB