Hydrogen peroxide and hydroxyl radicals mediate palmitate-induced cytotoxicity to hepatoma cells: Relation to mitochondrial permeability transition

Shireesh Srivastava, Christina Chan

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    Abstract

    We studied the toxicological responses of a human hepatoblastoma cell line (HepG2/C3A) to various free fatty acids (FFA) in order to identify the relation between reactive oxygen species (ROS) production and mitochondrial permeability transition (MPT). Exposure to the saturated FFA, palmitate, led to a time-dependent ROS production and hydrogen peroxide release as well as a loss of mitochondrial potential. The cytotoxicity of palmitate was significantly reduced by treating with scavengers of hydrogen peroxide, hydroxyl radical and the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone (POBN). Superoxide dismutase (SOD) mimics, nitric oxide scavenger, and inhibitor of de novo ceramide synthesis had no effect on the toxicity. MPT-inhibitor, cyclosporine, prevented the loss of mitochondrial potential but did not reduce the cytotoxicity. In contrast, inhibiting mitochondrial complexes I and III reduced the early potential loss and the cytotoxicity. These results suggest that palmitate-cytotoxicity to hepatoma cells is mediated through the production of H2O2 and *OH and independent of MPT.

    Original languageEnglish (US)
    Pages (from-to)38-49
    Number of pages12
    JournalFree Radical Research
    Volume41
    Issue number1
    DOIs
    StatePublished - Jan 2007

    Profile

    Palmitates
    Hydroxyl Radical
    Hydrogen Peroxide
    Hepatocellular Carcinoma
    Permeability
    Ethical Review
    Nonesterified Fatty Acids
    Reactive Oxygen Species
    Methacholine Compounds
    Hepatoblastoma
    Ceramides
    Electron Transport Complex III
    Toxicology
    Oxides
    Cyclosporine
    Superoxide Dismutase
    Nitric Oxide
    Fatty Acids
    Cell Line
    Acrodermatitis

    Keywords

    • Free fatty acids
    • Lipotoxicity
    • Mitochondrial permeability transition
    • Radical scavengers
    • Reactive oxygen species

    ASJC Scopus subject areas

    • Biochemistry

    Cite this

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    abstract = "We studied the toxicological responses of a human hepatoblastoma cell line (HepG2/C3A) to various free fatty acids (FFA) in order to identify the relation between reactive oxygen species (ROS) production and mitochondrial permeability transition (MPT). Exposure to the saturated FFA, palmitate, led to a time-dependent ROS production and hydrogen peroxide release as well as a loss of mitochondrial potential. The cytotoxicity of palmitate was significantly reduced by treating with scavengers of hydrogen peroxide, hydroxyl radical and the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone (POBN). Superoxide dismutase (SOD) mimics, nitric oxide scavenger, and inhibitor of de novo ceramide synthesis had no effect on the toxicity. MPT-inhibitor, cyclosporine, prevented the loss of mitochondrial potential but did not reduce the cytotoxicity. In contrast, inhibiting mitochondrial complexes I and III reduced the early potential loss and the cytotoxicity. These results suggest that palmitate-cytotoxicity to hepatoma cells is mediated through the production of H2O2 and *OH and independent of MPT.",
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