Role of oxidative stress, mitochondrial membrane potential, and calcium homeostasis in human lymphocyte death induced by nickel carbonate hydroxide in vitro.
When isolated human lymphocytes were treated in vitro with various concentrations of soluble form of nickel carbonate hydroxide (NiCH) (0-1 mM), at 37 degrees C for 4 h, both concentration- and time-dependent effects of NiCH on lymphocyte death were observed. Increased generation of hydrogen peroxide (H(2)O(2)), superoxide anion (O(2)(-) ), depletion of both no protein (NP-) and protein (P-) sulfhydryl (SH) contents and lipid peroxidation (LPO) were induced by NiCH. Pretreatment of lymphocytes with either catalase (H(2)O(2) scavenger), or deferoxamine (DFO) (iron chelator), or excess glutathione (GSH) (an antioxidant) not only significantly reduced the NiCH-induced generation of H(2)O(2) and LPO, but also increased the NP-SH and P-SH contents initially reduced by NiCH. NiCH-induced generation of excess O(2)(-) but not excess LPO was significantly reduced by pretreatment with superoxide dismutase (SOD). NiCH-induced lymphocyte death was significantly prevented by pre-treatment with either catalase, or dimethylthiourea/mannitol (hydroxyl radical scavengers), or DFO, or excess GSH/N-acetylcysteine. NiCH-induced lymphocyte death was also significantly prevented by pretreatment with excess SOD. Thus, various types of oxidative stresses play an important role in NiCH-induced lymphocyte death. Cotreatment with cyclosporin A (a specific inhibitor of alteration in mitochondrial membrane potential (DeltaPsi(m)) not only inhibited NiCH-induced alteration in DeltaPsi(m), but also significantly prevented Ni-compound-induced lymphocyte death. Furthermore, NiCH-induced destabilization of cellular calcium homeostasis. As such, NiCH-induced lymphocyte death was significantly prevented by modulating intracellular calcium fluxes such as Ca(2+) channel blockers and intracellular Ca(2+) antagonist. Thus, the mechanism of NiCH (soluble form)-induced activation of lymphocyte death signalling pathways involves not only the excess generation of different types of oxidative stress, but also the induction of alteration in DeltaPsi(m) 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, Main Station , P.O. Box 6128, H3C 3J7, Montréal, QC, Canada. 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; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D015227:Lipid Peroxidation; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000502:physiology*; D009532:Nickel / Q000633:toxicity*; D018384:Oxidative Stress / Q000502:physiology*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D013438:Sulfhydryl Compounds; D013481:Superoxides; D009532:Nickel; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione; D003676:Deferoxamine; D002118:Calcium; C030989:nickel carbonate