Role of oxidative stress, mitochondrial membrane potential, and calcium homeostasis in nickel subsulfide-induced human lymphocyte death in vitro.
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.
M'Bemba-Meka
Prosper
P
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. mp.mbemba@louisville.edu
Lemieux
Nicole
N
Chakrabarti
Saroj K
SK
D000328:Adult; D002118:Calcium / Q000378:metabolism*; D002374:Catalase / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000502:physiology; D008353:Mannitol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000502:physiology; D009532:Nickel / Q000633:toxicity*; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D016166:Free Radical Scavengers; D013481:Superoxides; D008353:Mannitol; D009532:Nickel; C038983:1,3-dimethylthiourea; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; D013890:Thiourea; D002118:Calcium; C017557:nickel subsulfide