Phenolic metabolites of benzene induced caspase‐dependent cytotoxicities to K562 cells accompanied with decrease in cell surface sialic acids
Phenolic metabolites of benzene induced caspase‐dependent cytotoxicities to K562 cells accompanied with decrease in cell surface sialic acids
复制标题
DOI：
10.1002/tox.21874
复制
发表时间：
2014-12
影响因子：
4.5
通讯作者：
Yan Wang;Guang-Yao Zhang;Qing-Ling Han;Jie-Xie Wang;Suriguga;Yang Li;Chun‐Hong Yu;Yi-Ran Li;Zong-Chun Yi
中科院分区：
文献类型：
--
作者：
Yan Wang;Guang-Yao Zhang;Qing-Ling Han;Jie-Xie Wang;Suriguga;Yang Li;Chun‐Hong Yu;Yi-Ran Li;Zong-Chun Yi
苯引起的红细胞生成抑制被认为是由于有毒代谢物的产生。目前，研究苯代谢物，包括苯酚、邻苯二酚、对苯二酚和1，2，4-苯三酚对K562红系祖细胞的毒性。K562细胞暴露于这些代谢物后，表现出明显的活力抑制和凋亡特征。各代谢产物均能显著提高caspase-3、-8和-9的活性，而caspase-3、-8和-9抑制剂可显著抑制苯代谢物诱导的磷脂酰丝氨酸暴露。这些代谢物也增加了细胞表面Fas和FasL的表达。苯代谢物作用于K562细胞后，细胞内活性氧水平升高，N-乙酰-L-半胱氨酸可明显拮抗苯代谢物的细胞毒性作用。有趣的是，对照K562细胞和苯酚暴露的细胞聚集在一起，但暴露于其他代谢物的细胞分散。进一步的分析表明，对苯二酚、邻苯二酚和1，2，4-苯三酚诱导细胞表面唾液酸水平下降，细胞表面唾液酸酶活性增加，而苯酚不引起唾液酸水平和唾液酸酶活性的变化。在对苯二酚、邻苯二酚和1，2，4-苯三酚处理的细胞中，唾液酸酶Neu3基因的表达水平升高，唾液酸基转移酶ST3GAL3基因的mRNA水平降低，而在苯酚处理的细胞中，这两个基因的mRNA水平没有变化。综上所述，这些苯代谢物主要通过caspase-8依赖的途径和ROS的产生诱导K562细胞的凋亡，唾液酸代谢可能参与了细胞的凋亡过程。©2013威利期刊公司Environ Toxicol 29：1437-1451,2014。
Benzene‐induced erythropoietic depression has been proposed to be due to the production of toxic metabolites. Presently, the cytotoxicities of benzene metabolites, including phenol, catechol, hydroquinone, and 1,2,4‐benzenetriol, to erythroid progenitor‐like K562 cells were investigated. After exposure to these metabolites, K562 cells showed significant inhibition of viability and apoptotic characteristics. Each metabolite caused a significant increase in activities of caspase‐3, ‐8, and ‐9, and pretreatment with caspase‐3, ‐8, and ‐9 inhibitors significantly inhibited benzene metabolites‐induced phosphatidylserine exposure. These metabolites also elevated expression of Fas and FasL on the cell surface. After exposure to benzene metabolites, K562 cells showed an increase in reactive oxygen species level, and pretreatment with N‐acetyl‐l‐cysteine significantly protected against the cytotoxicity of each metabolite. Interestingly, the control K562 cells and the phenol‐exposed cells aggregated together, but the cells exposed to other metabolites were scattered. Further analysis showed that hydroquione, catechol, and 1,2,4‐benzenetriol induced a decrease in the cell surface sialic acid levels and an increase in the cell surface sialidase activity, but phenol did not cause any changes in sialic acid levels and sialidase activity. Consistently, an increase in expression level of sialidase Neu3 mRNA and a decrease in mRNA level of sialyltransferase ST3GAL3 gene were detected in hydroquione‐, catechol‐, or 1,2,4‐benzenetriol‐treated cells, but no change in mRNA levels of two genes were found in phenol‐treated cells. In conclusion, these benzene metabolites could induce apoptosis of K562 cells mainly through caspase‐8‐dependent pathway and ROS production, and sialic acid metabolism might play a role in the apoptotic process. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1437–1451, 2014.