Mechanisms of arsenic-induced cross-tolerance to nickel cytotoxicity, genotoxicity, and apoptosis in rat liver epithelial cells
Mechanisms of arsenic-induced cross-tolerance to nickel cytotoxicity, genotoxicity, and apoptosis in rat liver epithelial cells
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DOI：
10.1093/toxsci/63.2.189
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发表时间：
2001-10-01
影响因子：
3.8
通讯作者：
Waalkes, MP
中科院分区：
文献类型：
--
作者：
Qu, W;Kasprzak, KS;Waalkes, MP
本研究旨在探讨砷转化细胞对镍的交叉耐受机制。慢性亚砷酸盐暴露（CAsE）细胞（TRL 1215细胞，已连续暴露于0.5 μ M亚砷酸盐20周或更长时间）和对照TRL 1215细胞都暴露于镍24小时，细胞活力测定代谢完整性。镍的LC 50在CAsE细胞中为608 +/- 32 μ M，而在对照细胞中为232 +/- 16 μ M，增加了2.6倍。用200 μ M镍处理CASE和对照细胞4小时，并使用ESR光谱法测量细胞自由基的产生。CAsE细胞羟自由基生成减少。在CAsE细胞中，指示脂质过氧化的硫代巴比妥酸反应物质和指示氧化性DNA损伤的8-氧代-2 '-脱氧鸟苷减少。使用Annexin/FITC的流式细胞术分析显示，镍诱导的CASE细胞凋亡减少。CASE细胞表现出对氧化剂诱导的毒性的普遍抗性，这一点通过对过氧化氢的敏感性显著降低来证明。有趣的是，细胞内还原型谷胱甘肽（GSH）水平显着增加，在CAsE细胞，当GSH耗尽，CAsE细胞失去其镍抗性。砷诱导的交叉耐受镍诱导的细胞毒性，遗传毒性和细胞凋亡的机制似乎与氧化剂诱导的损伤，可能是基于，至少部分地，在增加细胞GSH水平的广义电阻。
The purpose of the present study was to investigate the mechanism of cross-tolerance to nickel in arsenic-transformed cells. Chronic arsenite-exposed (CAsE) cells (TRL 1215 cells, which had been continuously exposed to 0.5 muM arsenite for 20 or more weeks) and control TRL 1215 cells were both exposed to nickel for 24 h, and cell viability was determined by metabolic integrity. The LC50 for nickel was 608 +/- 32 muM in CAsE cells as compared to 232 +/- 16 muM in control cells, a 2.6-fold increase. CAsE and control cells were treated with 200 muM nickel for 4 h and cellular-free radical production was measured using ESR spectrometry. Hydroxyl radical generation was decreased in CAsE cells. Thiobarbituric acid reactive substances, indicative of lipid peroxidation, and 8-oxo-2'-deoxyguanosine, indicative of oxidative DNA damage, were reduced in CAsE cells. Flow cytometric analysis using Annexin/FITC revealed that nickel-induced apoptosis was reduced in CAsE cells. CAsE cells showed generalized resistance to oxidant-induced toxicity as evidenced by a marked reduction in sensitivity to hydrogen peroxide. Interestingly, intracellular reduced glutathione (GSH) levels were significantly increased in CAsE cells, and when GSH was depleted, CAsE cells lost their nickel resistance. The mechanism of arsenic-induced cross-tolerance to cytotoxicity, genotoxicity, and apoptosis induced by nickel appears related to a generalized resistance to oxidant-induced injury, probably based, at least in part, in increased cellular GSH levels.