The endoplasmic reticulum is a target organelle for trivalent dimethylarsinic acid (DMA^III)-induced cytotoxicity

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• 作者：Hua Naranmandura^a ; ^{narenman@zju.edu.cn} ; Shi Xu^a ; Shota Koike^b ; Li Qiang Pan^a ; Bin Chen^c ; Yan Wei Wang^a ; Kanwal Rehman^a ; Bin Wu^a ; Zhe Chen^d ; Noriyuki Suzuki^b ; ^{n-suzuki@p.chiba-u.ac.jp}
• 关键词：iAsIII ; arsenite ; iAsV ; arsenate ; CHX ; cycloheximide ; DMAV ; dimethylarsinic acid ; DMAIII ; dimethylarsinous acid ; ER ; endoplasmic reticulum ; MMAIII ; monomethylarsonous acid ; ROS ; reactive oxygen species ; HPLC ; high performance liquid chromatography ; ICP MS
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2012
• 期刊代码：58_0041008x
• 类别：pha
• 出版时间：1 May, 2012
• 卷：260
• 期：3
• 页码：241-249
• 文件大小：1202 K

摘要

The purpose of present study was to characterize the endoplasmic reticulum stress and generation of ROS in rat liver RLC-16 cells by exposing to trivalent dimethylarsinous acid (DMA^III) and compared with that of trivalent arsenite (iAs^III) and monomethylarsonous acid (MMA^III). Protein kinase-like endoplasmic reticulum kinase (PERK) phosphorylation was significantly induced in cells exposed to DMA^III, while there was no change in phosphorylated PERK (P-PERK) detected in cells after exposure to iAs^III or MMA^III. The generation of reactive oxygen species (ROS) after DMA^III exposure was found to take place specifically in the endoplasmic reticulum (ER), while previous reports showed that ROS was generated in mitochondria following exposure to MMA^III. Meanwhile, cycloheximide (CHX) which is an inhibitor of protein biosynthesis strongly inhibited the DMA^III-induced intracellular ROS generation in the ER and the phosphorylation of PERK, suggesting the induction of ER stress probably occurs through the inhibition of the protein folding process. Activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) mRNA were induced by all three arsenic species, however, evidence suggested that they might be induced by different pathways in the case of iAs^III and MMA^III. In addition, ER resident molecular chaperone glucose-regulated protein78 (GRP78) was not affected by trivalent arsenicals, while it was induced in positive control only at high concentration (Thapsigargin;Tg), suggesting the GRP78 is less sensitive to low levels of ER stress. In summary, our findings demonstrate that the endoplasmic reticulum is a target organelle for DMA^III-induced cytotoxicity.