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Molecular Pharmacology

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Research ArticleArticle

Oxidative Stress and Cytotoxicity Induced by Ferric-Nitrilotriacetate in HepG2 Cells That Express Cytochrome P450 2E1

Koichi Sakurai and Arthur I. Cederbaum
Molecular Pharmacology December 1998, 54 (6) 1024-1035; DOI: https://doi.org/10.1124/mol.54.6.1024
Koichi Sakurai
Department of Biochemistry, Mount Sinai School of Medicine, New York, New York 10029
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Arthur I. Cederbaum
Department of Biochemistry, Mount Sinai School of Medicine, New York, New York 10029
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Abstract

Iron can potentiate the toxicity of ethanol. Ethanol increases the content of cytochrome P450 2E1 (CYP2E1), which generates reactive oxygen species, and transition metals such as iron are powerful catalysts of hydroxyl radical formation and lipid peroxidation. Experiments were carried out to attempt to link CYP2E1, iron, and oxidative stress as a potential mechanism by which iron increases ethanol toxicity. The addition of ferric-nitrilotriacetate (Fe-NTA) to a HepG2 cell line expressing CYP2E1 decreased cell viability, whereas little effect was observed in control cells not expressing CYP2E1. Toxicity in the CYP2E1-expressing cells was markedly enhanced after the depletion of glutathione. Lipid peroxidation was increased by Fe-NTA, especially in cell extracts and medium from the CYP2E1-expressing cells. Toxicity was completely prevented by vitamin E or by 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, which also decreased the lipid peroxidation. Levels of ATP were lowered by Fe-NTA, and this was associated with a decreased rate of oxygen consumption by permeabilized cells with substrates donating electrons to complexes I, II, and IV of the respiratory chain. This mitochondrial damage was prevented by vitamin E. Toxicity was accompanied by DNA fragmentation, and this fragmentation was prevented by antioxidants. Overexpression of bcl-2 decreased the toxicity and DNA fragmentation produced by the combination of CYP2E1 plus Fe-NTA, as did a peptide inhibitor of caspase 3. These results suggest that elevated generation of reactive oxygen species in HepG2 cells expressing CYP2E1 leads to lipid peroxidation in the presence of iron, and the ensuing prooxidative state damages mitochondria, releasing factors that activate caspase 3, leading to a loss in cell viability and DNA fragmentation.

Footnotes

    • Received June 12, 1998.
    • Accepted August 27, 1998.
  • Send reprint requests to: Dr. Arthur I. Cederbaum, Department of Biochemistry, Box 1020, Mount Sinai School of Medicine, New York, NY 10029. E-mail:acederb{at}smtplink.mssm.edu

  • This study was supported by United States Public Health Service Grants AA03312 and AA06610 from The National Institute on Alcohol Abuse and Alcoholism.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (6)
Molecular Pharmacology
Vol. 54, Issue 6
1 Dec 1998
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Research ArticleArticle

Oxidative Stress and Cytotoxicity Induced by Ferric-Nitrilotriacetate in HepG2 Cells That Express Cytochrome P450 2E1

Koichi Sakurai and Arthur I. Cederbaum
Molecular Pharmacology December 1, 1998, 54 (6) 1024-1035; DOI: https://doi.org/10.1124/mol.54.6.1024

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Research ArticleArticle

Oxidative Stress and Cytotoxicity Induced by Ferric-Nitrilotriacetate in HepG2 Cells That Express Cytochrome P450 2E1

Koichi Sakurai and Arthur I. Cederbaum
Molecular Pharmacology December 1, 1998, 54 (6) 1024-1035; DOI: https://doi.org/10.1124/mol.54.6.1024
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