Yuan Tongkuo, Sun Jiaojiao, Tian Jingjing, Hu Jia, Yin Huancai, Yin Jian
CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, PR China; Jinan Guo Ke Medical Technology Development Co., Ltd, PR China.
CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, PR China; University of Science and Technology of China, Hefei, Anhui 230026, PR China.
Toxicology. 2021 May 15;455:152762. doi: 10.1016/j.tox.2021.152762. Epub 2021 Mar 22.
This paper aimed to systemically investigate the role of adenosine triphosphate-binding cassette (ABC transporters) in the detoxification of non-substrate nanoparticles including titanium dioxide (n-TiO, 5-10 nm) and gold (AuNPs, 3 nm, 15 nm, and 80 nm, named as Au-3, Au-15 and Au-80) in human lung cancer (A549) and human cervical cancer (HeLa) cells. All these nanoparticles were of larger hydrophilic diameters than the channel sizes of ABC transporters, thus should not be the substrates of membrane proteins. After 24-h treatment, they induced significant cytotoxicity as reflected by the reduction in cell viability and glutathione (GSH) contents, as well as the increase in reactive oxygen species (ROS) level. At median-lethal concentrations (10 mg/L n-TiO, 2 mg/L Au-3, 5 mg/L Au-15, and 10 mg/L Au-80 for A549 cells; 20 mg/L n-TiO, 2 mg/L Au-3, 5 mg/L Au-15, and 10 mg/L Au-80 for Hela cells), all the nanoparticles significantly induced the gene expressions and activities of ABC transporters including P-glycoprotein (PGP) and multidrug resistance associated protein 1 (MRP1). Addition of transporter inhibitors enhanced the ROS levels produced by nanoparticles, but didn't alter their death-inducing effects and intracellular accumulations. With specific suppressors, transcription factors like nuclear factor-erythroid 2-related factor-2 (NRF2) and pregnane X receptor (PXR) were proved to be important in the induction of ABC transporters by nanoparticles. After all, this paper revealed a damage-dependent modulation of ABC transporters by non-substrate nanoparticles. The up-regulated ABC transporters could help in reducing the oxidative stress produced by nanoparticles. Such information should be useful in assessing the environmental risk of nanoparticles, as well as their interactions with other chemical toxicants or drugs.
本文旨在系统研究三磷酸腺苷结合盒转运体（ABC转运体）在人肺癌（A549）细胞和人宫颈癌（HeLa）细胞中对包括二氧化钛（n-TiO，5-10nm）和金（AuNPs，3nm、15nm和80nm，分别命名为Au-3、Au-15和Au-80）在内的非底物纳米颗粒解毒过程中的作用。所有这些纳米颗粒的亲水性直径均大于ABC转运体的通道尺寸，因此不应是膜蛋白的底物。经过24小时处理后，它们诱导了显著的细胞毒性，表现为细胞活力和谷胱甘肽（GSH）含量降低，以及活性氧（ROS）水平升高。在半数致死浓度下（A549细胞为10mg/L n-TiO、2mg/L Au-3、5mg/L Au-15和10mg/L Au-80；HeLa细胞为20mg/L n-TiO、2mg/L Au-3、5mg/L Au-15和10mg/L Au-80），所有纳米颗粒均显著诱导了包括P-糖蛋白（PGP）和多药耐药相关蛋白1（MRP1）在内的ABC转运体的基因表达和活性。添加转运体抑制剂可增强纳米颗粒产生的ROS水平，但未改变其诱导细胞死亡的作用和细胞内蓄积情况。使用特异性抑制剂后，核因子红细胞2相关因子2（NRF2）和孕烷X受体（PXR）等转录因子被证明在纳米颗粒诱导ABC转运体过程中起重要作用。总之，本文揭示了非底物纳米颗粒对ABC转运体的损伤依赖性调节。上调的ABC转运体有助于降低纳米颗粒产生的氧化应激。这些信息对于评估纳米颗粒的环境风险及其与其他化学毒物或药物的相互作用应具有重要意义。
