Indole-3-carbinol enhances oxidative stress responses resulting in the induction of preneoplastic liver cell lesions in partially hepatectomized rats initiated with diethylnitrosamine
Indole-3-carbinol enhances oxidative stress responses resulting in the induction of preneoplastic liver cell lesions in partially hepatectomized rats initiated with diethylnitrosamine
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DOI：
10.1016/j.tox.2011.03.003
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发表时间：
2011-05-10
期刊：
影响因子：
4.5
通讯作者：
Mitsumori, Kunitoshi
中科院分区：
文献类型：
--
作者：
Shimamoto, Keisuke;Dewa, Yasuaki;Mitsumori, Kunitoshi
采用大鼠中期肝癌模型，研究了十字花科蔬菜中的细胞色素P450（P450）1A诱导剂吲哚-3-甲醇（I3 C）的促肝癌作用。6周龄的雄性F344大鼠接受N-二乙基亚硝胺（DEN）的腹膜内注射，并从DEN开始后2周开始喂食含有0（单独DEN）、0.25、0.50或1.0%I3C的饮食8周。与单独DEN组相比，给予0.5%I3C或更多的大鼠肝脏中谷胱甘肽S-转移酶胎盘型（GST-P）阳性的肝细胞灶的数量和面积显著增加。在0.25%I3C组中，GST-P阳性灶的数量也增加。增殖细胞核抗原（PCNA）阳性的肝细胞的数量显着增加，在所有I3 C组相比，在DEN单独组。实时RT-PCR分析显示，I3 C不仅增加了Cyp 1a 1的转录水平，还增加了芳烃受体（AhR）和/或核因子（红细胞衍生2）样2（Nrf 2）基因组的转录水平，例如Cyp 1a 2、Cyp 1b 1、Ugt 1a 6、Nrf 2、Nqo 1、Gsta 5、Gstm 2、Ggt 1和Gpx 2。与单独DEN组相比，所有I3 C处理组中微粒体组分中的活性氧（ROS）显著增加，硫代巴比妥酸反应物质（TBARS）水平和8-羟基-2 '-脱氧鸟苷（8-OHdG）含量分别在所有I3 C处理组和1.0%I3C组中显著增加。这些结果表明，I3 C是一种AhR激活剂，并增强微粒体ROS的产生，导致Nrf 2基因电池的上调，但产生的氧化应激克服了Nrf 2相关基因的抗氧化作用。这种“氧化还原失衡”随后通过增强大鼠细胞增殖诱导肝肿瘤促进作用。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
The liver tumor-promoting effects of indole-3-carbinol (I3C), a cytochrome P450 (CYP)1A inducer found in cruciferous vegetables, were investigated using a medium-term hepatocarcinogenesis model in rats. Six-week-old male F344 rats received an intraperitoneal injection of N-diethylnitrosamine (DEN) and were fed a diet containing 0 (DEN-alone), 0.25, 0.50 or 1.0% of I3C for 8 weeks from 2 weeks after DEN-initiation. The number and area of liver cell foci positive for glutathione S-transferase placental form (GST-P) significantly increased in the livers of rats given 0.5% I3C or more, compared to those in the DEN-alone group. The number of GST-P positive foci also increased in the 0.25% I3C group. The number of liver cells positive for proliferating cell nuclear antigen (PCNA) significantly increased in all I3C groups compared to that in the DEN-alone group. Real-time RT-PCR analysis showed that I3C increased transcript levels of not only Cyp1a1 but also aryl hydrocarbon receptor (AhR) and/or nuclear factor (erythroid-derived 2)-like 2 (Nrf2) gene batteries, such as Cyp1a2, Cyp1b1, Ugt1a6, Nrf2, Nqo1, Gsta5, Gstm2, Ggt1 and Gpx2. Reactive oxygen species (ROS) in the microsomal fraction significantly increased in all I3C-treated groups compared to the DEN-alone group, and thiobarbituric acid-reactive substances (TBARS) levels and 8-hydroxy-2'-deoxyguanosine (8-OHdG) content significantly increased in all of the I3C-treated groups and 1.0% I3C group, respectively. These results suggest that I3C is an AhR activator and enhances microsomal ROS production resulting in the upregulation of Nrf2 gene batteries, but the oxidative stress generated overcomes the antioxidant effect of Nrf2-related genes. Such 'a redox imbalance' subsequently induces liver tumor-promoting effects by enhancing cellular proliferation in rats. (C) 2011 Elsevier Ireland Ltd. All rights reserved.