Acute Exposure to 3-Methylcholanthrene Induces Hepatic Oxidative Stress via Activation of the Nrf2/ARE Signaling Pathway in Mice
Acute Exposure to 3-Methylcholanthrene Induces Hepatic Oxidative Stress via Activation of the Nrf2/ARE Signaling Pathway in Mice
复制标题
小鼠急性暴露于 3-甲基胆蒽通过激活 Nrf2/ARE 信号通路诱导肝脏氧化应激
DOI：
10.1002/tox.21870
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发表时间：
2014-12-01
影响因子：
4.5
通讯作者：
Fu, Zhengwei
中科院分区：
文献类型：
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作者：
Jin, Yuanxiang;Miao, Wenyu;Fu, Zhengwei
多环芳烃（PAH）是环境中最常见的污染物。 PAH 毒性的主要关注点是它们能够激活芳烃受体 (AhR) 介导的途径并导致不同生物体致癌。然而，多环芳烃对哺乳动物系统抗氧化系统的影响仅受到有限的关注。在本研究中，我们观察到给小鼠腹腔注射100 mg/kg 3-甲基胆蒽（3MC）显着增加了活性氧（ROS）水平和丙二醛（MDA）含量，降低了谷胱甘肽（GSH）含量和总抗氧化能力（T-AOC）活性，表明肝脏中诱导了严重的氧化应激 的老鼠。然后，氧化应激信号通过增强Nrf2、p38和Erk2的mRNA水平来激活核因子红细胞2相关因子2/抗氧化反应元件(Nrf2/ARE)通路。此外，用3MC处理24小时后，Nrf2/ARE靶基因的mRNA水平显着增加，包括谷胱甘肽过氧化物酶（Gpx）、谷胱甘肽还原酶（GR）、谷胱甘肽合成酶（GS）、NAD（P）H：醌氧化还原酶1（Nqo1）、超氧化物歧化酶1（Sod1）和Sod2。 3MC治疗后24小时，肝脏NQO1水平以及GR和GS活性也显着增强。由于哺乳动物组织中 NQO1 的表达受到 Nrf2/ARE 和 AhR/XRE 的共同调节，因此 NQO1 可能在防止 3MC 诱导的氧化应激中发挥重要作用。综上所述，我们的研究结果表明，急性暴露于 3MC 会改变肝细胞中的细胞氧化还原平衡，从而触发 Nrf2 调节的抗氧化反应，这可能代表针对 PAH 诱导的氧化应激的适应性细胞防御机制。 (c) 2013 年 Wiley periodicals, Inc.Environ Toxicol 29：1399-1408，2014 年。
Polycyclic aromatic hydrocarbons (PAHs) are the most common contaminants in the environment. The primary focus on the toxicity of PAHs is their ability to activate the aryl hydrocarbon receptor (AhR)-mediated pathway and lead to carcinogenesis in different organisms. However, the influence of PAHs on the antioxidant system in mammalian systems has received only limited attention. In the present study, we observed that the intraperitoneal injection of 100 mg/kg 3-methylcholanthrene (3MC) into mice significantly increased reactive oxygen species (ROS) levels and malondialdehyde (MDA) contents and decreased glutathione (GSH) contents and the activity of total antioxidant capacity (T-AOC), indicating that serious oxidative stress had been induced in the liver of mice. Then, the oxidative stress signal activated the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway by enhancing the mRNA levels of Nrf2, p38, and Erk2. Moreover, the mRNA levels of Nrf2/ARE target genes, including glutathione peroxidase (Gpx), glutathione reductase (GR), glutathione synthetase (GS), NAD(P)H: quinone oxidoreductase 1 (Nqo1), superoxide dismutase 1 (Sod1), and Sod2, increased significantly after treatment with 3MC for 24 hours. The hepatic levels of NQO1 and the activities of GR and GS were also significantly enhanced at 24 hours after 3MC treatment. Because the expression of NQO1 is co-regulated by Nrf2/ARE and AhR/XRE in mammalian tissues, NQO1 may play an important role in protecting against the oxidative stress induced by 3MC. Taken together, our findings suggested that acute exposure to 3MC altered the cellular redox balance in hepatocytes to trigger Nrf2-regulated antioxidant responses, which may represent an adaptive cell defense mechanism against the oxidative stress induced by PAHs. (c) 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1399-1408, 2014.