Role of oxidative stress, mitochondrial membrane potential, and calcium homeostasis in nickel sulfate-induced human lymphocyte death in vitro.
When isolated human lymphocytes were treated in vitro with various concentrations of nickel sulfate (NiSO4) (0-4 mM) at 37 degrees C for 4 h, both concentration- and time-dependent effects of NiSO4 on lymphocyte death were observed. Increased generation of hydrogen peroxide, depletion of both nonprotein and protein sulfhydryl contents, and lipid peroxidation were induced by NiSO4. NiSO4-induced lymphocyte death was significantly prevented by pre-treatment with either catalase, or dimethylthiourea/mannitol, or deferoxamine, or excess glutathione/N-acetylcysteine. Cotreatment with cyclosporin A (a specific inhibitor of mitochondrial membrane potential) not only inhibited NiSO4-induced mitochondrial membrane potential, but also significantly prevented Ni compound-induced lymphocyte death. NiSO4-induced lymphocyte death was also significantly prevented by modulating intracellular calcium fluxes using both Ca2+ channel blockers and intracellular Ca2+ antagonist. Thus, the mechanism of NiSO4-induced activation of lymphocyte death signalling pathways involves not only the excess generation of different types of oxidative stress but also NiSO4-induced loss of mitochondrial membrane potential and destabilization of cellular calcium homeostasis as well.
M'Bemba-Meka
Prosper
P
Human Toxicology Research Group (TOXHUM), Department of Environmental and Occupational Health, Faculty of Medicine, Université de Montréal, P.O. Box 6128, Main Station, Montréal, Que., Canada H3C 3J7.
Lemieux
Nicole
N
Chakrabarti
Saroj K
SK
D000111:Acetylcysteine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D008353:Mannitol / Q000494:pharmacology; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009532:Nickel / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D008353:Mannitol; C029938:nickel sulfate; D009532:Nickel; D016572:Cyclosporine; C038983:1,3-dimethylthiourea; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione; D013890:Thiourea; D003676:Deferoxamine; D002118:Calcium; D000111:Acetylcysteine