The effects of hexavalent chromium on thioredoxin reductase and peroxiredoxins in human bronchial epithelial cells.
The effects of hexavalent chromium on thioredoxin reductase and peroxiredoxins in human bronchial epithelial cells.
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DOI：
10.1016/j.freeradbiomed.2009.08.015
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发表时间：
2009-11-15
影响因子：
7.4
通讯作者：
Myers, Charles R.
中科院分区：
文献类型：
--
作者：
Myers, Judith M.;Myers, Charles R.
六价铬[Cr（VI）]化合物（例如铬酸盐）的吸入暴露在许多与铬相关的行业及其周围环境中受到关注。支气管上皮直接暴露于吸入的Cr（VI）。Cr（VI）物质容易进入细胞内，在那里它们被还原为活性Cr物质，这也可能有助于活性氧物质（ROS）的产生。硫氧还蛋白（Trx）系统促进细胞存活，并在维持细胞内巯基氧化还原平衡中发挥重要作用。先前对正常人支气管上皮细胞（BEAS-2B）的研究表明，铬酸盐导致Trx 1和Trx 2的剂量和时间依赖性氧化。Trx使许多细胞内蛋白质保持还原，包括过氧化物酶（Prx）。Prx 1（胞质）和Prx 3（线粒体）被氧化的Cr（VI）处理，氧化所有，或几乎所有，各自的Trx。因此，Prx氧化可能是缺乏Trx还原当量的结果。Trx还原酶（TrxR）主要维持Trx处于还原状态。Cr（VI）引起TrxR的显著抑制，但TrxR蛋白水平保持不变。去除残留的Cr（VI）或NADPH（TrxR的内源性电子供体）不能逆转TrxR的抑制。相反，Trx 1，Trx 2和Prx 3的氧化是可逆的二硫化物还原剂。Cr（VI）处理的细胞中TrxR的长期抑制可能有助于Trxs和Prxs的持续氧化。还原型Trx与凋亡信号激酶（ASK 1）的N端结构域结合，使ASK 1保持非活性。Cr（VI）处理，显着氧化Trx 1导致显着的解离Trx 1从ASK 1。总的来说，Cr（VI）对支气管上皮中Trxs，Prxs和TrxR的氧化还原状态和功能的影响可能对氧化还原敏感的细胞信号传导和对氧化剂损伤的耐受性具有重要意义。
Inhalational exposure to hexavalent chromium [Cr(VI)] compounds (e.g. chromates) is of concern in many Cr-related industries and their surrounding environments. The bronchial epithelium is directly exposed to inhaled Cr(VI). Cr(VI) species gain easy access inside cells where they are reduced to reactive Cr species which may also contribute to the generation of reactive oxygen species (ROS). The thioredoxin (Trx) system promotes cell survival and has a major role in maintaining intracellular thiol redox balance. Previous studies with normal human bronchial epithelial cells (BEAS-2B) demonstrated that chromates cause dose- and time-dependent oxidation of Trx1 and Trx2. The Trxs keep many intracellular proteins reduced including the peroxiredoxins (Prx). Prx1 (cytosolic) and Prx3 (mitochondrial) were oxidized by Cr(VI) treatments that oxidized all, or nearly all, of the respective Trxs. Prx oxidation is therefore likely the result of a lack of reducing equivalents from Trx. Trx reductases (TrxR) maintain the Trxs largely in the reduced state. Cr(VI) caused pronounced inhibition of TrxR, but the levels of TrxR protein remained unchanged. The inhibition of TrxR was not reversed by removal of residual Cr(VI) or by NADPH, the endogenous electron donor for TrxR. In contrast, the oxidation of Trx1, Trx2, and Prx3 were reversible by disulfide reductants. Prolonged inhibition of TrxR in Cr(VI)-treated cells might contribute to the sustained oxidation of Trxs and Prxs. Reduced Trx binds to an N-terminal domain of apoptosis signaling kinase (ASK1), keeping ASK1 inactive. Cr(VI) treatments that significantly oxidized Trx1 resulted in pronounced dissociation of Trx1 from ASK1. Overall, the effects of Cr(VI) on the redox state and function of the Trxs, Prxs, and TrxR in the bronchial epithelium could have important implications for redox-sensitive cell signaling and tolerance to oxidant insults.
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