Reduction of arsenic-induced cytotoxicity through Nrf2/HO-1 signaling in HepG2 cells
Reduction of arsenic-induced cytotoxicity through Nrf2/HO-1 signaling in HepG2 cells
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DOI：
10.2131/jts.35.419
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发表时间：
2010-06-01
影响因子：
2
通讯作者：
Kumagai, Yoshito
中科院分区：
文献类型：
--
作者：
Abiko, Yumi;Shinkai, Yasuhiro;Kumagai, Yoshito
我们以前的研究表明，Nrf 2是一个关键的转录因子在细胞防御无机砷（iAsIII）。然而，血红素加氧酶-1（HO-1），这是由Nrf 2调节，iAsIII诱导的细胞毒性的作用知之甚少。为了解决这个问题，我们研究了HO-1对iAsIII介导的Nrf 2活化的贡献，以及在HepG 2细胞中对iAsIII细胞毒性的保护作用。暴露于iAsIII（10 μ M）的HepG 2细胞引起持续诱导HO-1伴随着长期Nrf 2激活，而siRNA介导的敲低HO-1减少长期Nrf 2激活。用HO-1 siRNA或HO抑制剂（锡原卟啉IX）预处理显著增强iAsIII诱导的细胞毒性。这些结果表明，iAsIII诱导的HO-1似乎，至少部分，作为一个Nrf 2激活的正反馈调节，从而减少其在HepG 2细胞的细胞毒性。
Our previous study indicated that Nrf2 is a key transcription factor in cellular defenses against inorganic arsenite (iAsIII). However, the role of heme oxygenase-1 (HO-1), which is regulated by Nrf2, in iAsIII-induced cytotoxicity is poorly understood. To address this issue, we examined the contribution of HO-1 to iAsIII-mediated Nrf2 activation and in protection against iAsIII cytotoxicity in HepG2 cells. Exposure of HepG2 cells to iAsIII (10 mu M) caused persistent induction of HO-1 accompanied by prolonged Nrf2 activation, whereas siRNA-mediated knockdown of HO-I decreased prolonged Nrf2 activation. Pretreatment with either HO-1 siRNA or HO inhibitor (tin protoporphyrin IX) significantly enhanced iAsIII-induced cytotoxicity. These results suggest that iAsIII-induced HO-1 appears, at least in part, to act as a positive feedback regulator of Nrf2 activation, thereby diminishing its cytotoxicity in HepG2 cells.