M'Bemba-Meka Prosper, Lemieux Nicole, Chakrabarti Saroj K
Human Toxicology Research Group (TOXHUM), Department of Environmental and Occupational Health, Faculty of Medicine, Université de Montréal PO Box 6128, Main Station, Montréal, Québec, Canada H3C 3J7.
Sci Total Environ. 2006 Oct 1;369(1-3):21-34. doi: 10.1016/j.scitotenv.2006.04.007. Epub 2006 Jun 15.
When isolated human lymphocytes were treated in vitro either with various concentrations (0-2 mM) of soluble form of nickel subsulfide (Ni3S2) at 37 degrees C for 4 h or at various times (0-240 min), both concentration- and time-dependent effects of Ni3S2 on lymphocyte death were observed. Increased generation of hydrogen peroxide (H2O2), and superoxide anion (O2-), lipid peroxidation and depletion of both nonprotein (NP-) and protein (P-) sulfhydryl (SH) contents were induced by 1 mM Ni3S2. Ni3S2-induced lymphocyte death was significantly prevented by pre-treatment with either catalase (a H2O2 scavenger), or superoxide dismutase (scavenger of O2- radical), or dimethylthiourea/mannitol (hydroxyl radical scavengers), or deferoxamine (iron-chelator), or glutathione/N-acetylcysteine. Co-treatment with cyclosporin A (a mitochondrial membrane potential' inhibitor) inhibited Ni3S2-induced disturbances in mitochondrial membrane potential, and significantly prevented Ni3S2-induced lymphocyte death. Ni3S2-induced lymphocyte death was also significantly prevented by modulating intracellular calcium fluxes using both Ca2+ channel blockers and intracellular Ca2+ antagonists. Thus, the mechanism of soluble Ni3S2-induced activation of lymphocyte death signalling pathways involves increasing generation of different types of oxidative stress, disturbances in mitochondrial membrane potential and cellular calcium homeostasis' destabilization.
当将分离的人淋巴细胞在体外于37℃下用不同浓度（0 - 2 mM）的硫化亚镍（Ni3S2）可溶形式处理4小时或在不同时间（0 - 240分钟）处理时，观察到Ni3S2对淋巴细胞死亡的浓度和时间依赖性效应。1 mM Ni3S2可诱导过氧化氢（H2O2）、超氧阴离子（O2-）生成增加，脂质过氧化以及非蛋白（NP-）和蛋白（P-）巯基（SH）含量的消耗。预先用过氧化氢酶（一种H2O2清除剂）、超氧化物歧化酶（O2-自由基清除剂）、二甲基硫脲/甘露醇（羟基自由基清除剂）、去铁胺（铁螯合剂）或谷胱甘肽/N-乙酰半胱氨酸处理可显著预防Ni3S2诱导的淋巴细胞死亡。与环孢素A（一种线粒体膜电位抑制剂）共同处理可抑制Ni3S2诱导的线粒体膜电位紊乱，并显著预防Ni3S2诱导的淋巴细胞死亡。使用Ca2+通道阻滞剂和细胞内Ca2+拮抗剂调节细胞内钙通量也可显著预防Ni3S2诱导的淋巴细胞死亡。因此，可溶性Ni3S2诱导淋巴细胞死亡信号通路激活的机制涉及增加不同类型氧化应激的产生、线粒体膜电位紊乱和细胞钙稳态的破坏。
