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Research ArticleTOXICOLOGY

Adenovirus-Mediated Overexpression of Catalase in the Cytosolic or Mitochondrial Compartment Protects against Toxicity Caused by Glutathione Depletion in HepG2 Cells Expressing CYP2E1

Montserrat Marı́, Jingxiang Bai and Arthur I. Cederbaum
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 111-118; DOI: https://doi.org/10.1124/jpet.301.1.111
Montserrat Marı́
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Jingxiang Bai
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Arthur I. Cederbaum
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Abstract

Induction of cytochrome P450 CYP2E1 by ethanol appears to be one of the mechanisms by which ethanol creates a state of oxidative stress. Glutathione (GSH) is a key cellular antioxidant that detoxifies reactive oxygen species. Depletion of GSH, especially mitochondrial GSH, is believed to play a role in the ethanol-induced liver injury. Previous results reported that depletion of GSH by buthionine-(S,R)-sulfoximine (BSO) treatment caused apoptosis and necrosis in HepG2 cells, which overexpress CYP2E1. In the current work, adenoviral infection with vectors that resulted in expression of catalase either in the cytosol or mitochondrial compartments was able to abolish the loss of mitochondrial membrane potential or damage to mitochondria observed in HepG2 cells overexpressing CYP2E1 that were treated with BSO. Loss of cell viability, either necrotic or apoptotic, was also prevented by the catalase overexpression after infection with the adenoviral vectors. The protective effects of catalase were associated with the suppression of the increase in the production of reactive oxygen species and of mitochondrial lipid peroxidation observed after GSH depletion. These results reveal a prominent role for H2O2 as a mediator in the cytotoxicity observed after depletion of GSH in HepG2 cells overexpressing CYP2E1. Damage to mitochondria may be a critical step for cellular toxicity by CYP2E1-derived reactive oxygen species.

Footnotes

  • This study was supported by U.S. Public Health Service Grant AA 06610 from the National Institute on Alcohol Abuse and Alcoholism.

  • Abbreviations:
    GSH
    glutathione
    BSO
    buthionine-(S,R)-sulfoximine
    Ad
    adenovirus
    mCAT
    mitochondrial catalase
    MnSOD
    manganese-superoxide dismutase
    cCAT
    cytosolic catalase
    ROS
    reactive oxygen species
    DCF-DA
    2′-7′-dichlorofluorescein diacetate
    Ad-Null
    adenovirus containing no cDNA
    PBS
    phosphate-buffered saline
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    MDA
    malondialdehyde
    PI
    propidium iodide
    AnnV
    Annexin V
    FITC
    fluorescein isothiocyanate
    Rh123
    rhodamine 123
    • Received October 10, 2001.
    • Accepted December 13, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Research ArticleTOXICOLOGY

Adenovirus-Mediated Overexpression of Catalase in the Cytosolic or Mitochondrial Compartment Protects against Toxicity Caused by Glutathione Depletion in HepG2 Cells Expressing CYP2E1

Montserrat Marı́, Jingxiang Bai and Arthur I. Cederbaum
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 111-118; DOI: https://doi.org/10.1124/jpet.301.1.111

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Research ArticleTOXICOLOGY

Adenovirus-Mediated Overexpression of Catalase in the Cytosolic or Mitochondrial Compartment Protects against Toxicity Caused by Glutathione Depletion in HepG2 Cells Expressing CYP2E1

Montserrat Marı́, Jingxiang Bai and Arthur I. Cederbaum
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 111-118; DOI: https://doi.org/10.1124/jpet.301.1.111
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