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Role of oxidative stress, mitochondrial membrane potential, and calcium homeostasis in human lymphocyte death induced by nickel carbonate hydroxide in vitro

  • Molecular Toxicology
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Abstract

When isolated human lymphocytes were treated in vitro with various concentrations of soluble form of nickel carbonate hydroxide (NiCH) (0–1 mM), at 37°C for 4 h, both concentration- and time-dependent effects of NiCH on lymphocyte death were observed. Increased generation of hydrogen peroxide (H2O2), 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 (H2O2 scavenger), or deferoxamine (DFO) (iron chelator), or excess glutathione (GSH) (an antioxidant) not only significantly reduced the NiCH-induced generation of H2O2 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 (ΔΨm) not only inhibited NiCH-induced alteration in ΔΨm, 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 Ca2+ channel blockers and intracellular Ca2+ 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 ΔΨm and destabilization of cellular calcium homeostasis as well.

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Abbreviations

NiCH:

Nickel carbonate hydroxide

GSH:

Glutathione

DFO:

Deferoxamine

DMTU:

Dimethylthiourea

NP-SH:

No protein sulfhydryl

P-SH:

Protein sulfhydryl

SOD:

Superoxide dismutase

LPO:

Lipid peroxidation

ΔΨm :

Mitochondrial membrane potential

[Ca2+]i :

Free intracellular calcium level

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Acknowledgements

The authors sincerely thank Sainte-Justine Hospital, for obtaining blood samples from donors and from the laboratory of vascular immunology of Dr. Genevieve Rainier and Dr. Jean-Claude Mamputu of CHUM, Research Center, Notre-Dame Hospital, Montreal.

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Authors and Affiliations

  1. 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

    Prosper M’Bemba-Meka & Saroj K. Chakrabarti

  2. Department of Pathology and Cellular Biology, Faculty of Medicine, Université de Montréal, Main Station , P.O. Box 6128, H3C 3J7, Montréal, QC, Canada

    Nicole Lemieux

  3. Department of Pharmacology and Toxicology, Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY, 40292, USA

    Prosper M’Bemba-Meka

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  1. Prosper M’Bemba-Meka
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Correspondence to Prosper M’Bemba-Meka.

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M’Bemba-Meka, P., Lemieux, N. & Chakrabarti, S.K. Role of oxidative stress, mitochondrial membrane potential, and calcium homeostasis in human lymphocyte death induced by nickel carbonate hydroxide in vitro. Arch Toxicol 80, 405–420 (2006). https://doi.org/10.1007/s00204-006-0060-x

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