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Molecular Pharmacology

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Research ArticleArticle

Synergistic Toxicity of Iron and Arachidonic Acid in HepG2 Cells Overexpressing CYP2E1

Andres A. Caro and Arthur I. Cederbaum
Molecular Pharmacology October 2001, 60 (4) 742-752;
Andres A. Caro
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Arthur I. Cederbaum
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Abstract

Priming of the liver for ethanol-induced injury, by nutrients such as polyunsaturated fat and iron, plays a key role in alcoholic liver disease. The objective of this work was to evaluate the effect of the combination of Fe-nitrilotriacetic acid (Fe-NTA) and arachidonic acid (AA) on the viability of HepG2 cells (E47 cells) transfected to express human CYP2E1. Cells were plated, preloaded with arachidonic acid, washed, and exposed to Fe-NTA for variable periods. Fe-NTA (10 μM) or AA (5 μM) alone showed low toxicity to E47 cells (18 and 8%, respectively, at 24 h), whereas the combination produced synergistic injury (62% toxicity at 24 h). Exposure of cells not expressing any cytochrome P450 (P450), or HepG2-C3A4 cells (expressing CYP3A4) to 10 μM Fe-NTA plus 5 μM AA produced lower toxicity (14 and 32%, respectively), demonstrating a role for P450, and in particular CYP2E1, in the development of toxicity by exposure to Fe + AA. Lipid peroxidation was induced in the E47 cells exposed to Fe plus arachidonic acid and the synergistic toxicity was prevented by antioxidants, which also decreased lipid peroxidation. Damage to mitochondria plays a role in the CYP2E1-dependent toxicity of Fe + AA, because the mitochondrial transmembrane potential decreased early in the process, and cyclosporin A prevented the toxicity. Toxicity in E47 cells exposed to Fe + AA is mainly necrotic in nature. Hepatocytes from pyrazole-treated rats, with high levels of CYP2E1, were more sensitive to Fe + AA toxicity than were saline control hepatocytyes. The results presented suggest that low concentrations of Fe and AA can act as priming or sensitizing factors for CYP2E1-induced injury in HepG2 cells, and such interactions may play a role in alcohol-induced liver injury.

Footnotes

  • These studies were supported by National Institute on Alcohol Abuse and Alcoholism Grant AA06610.

  • Abbreviations:
    ROS
    reactive oxygen species
    PUFA
    polyunsaturated fatty acid
    NTA
    nitrilotriacetic acid
    P450
    cytochrome P450
    PBS
    phosphate-buffered saline
    MEM
    minimal essential medium
    AA
    arachidonic acid
    MTT
    3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
    LDH
    lactate dehydrogenase
    Rh123
    rhodamine 123
    PI
    propidium iodide
    ANOVA
    analysis of variance
    TBARS
    thiobarbituric acid reactive substances
    DMSO
    dimethyl sulfoxide
    PT
    permeability transition
    TNF
    tumor necrosis factor
    • Received February 21, 2001.
    • Accepted June 26, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (4)
Molecular Pharmacology
Vol. 60, Issue 4
1 Oct 2001
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Research ArticleArticle

Synergistic Toxicity of Iron and Arachidonic Acid in HepG2 Cells Overexpressing CYP2E1

Andres A. Caro and Arthur I. Cederbaum
Molecular Pharmacology October 1, 2001, 60 (4) 742-752;

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Research ArticleArticle

Synergistic Toxicity of Iron and Arachidonic Acid in HepG2 Cells Overexpressing CYP2E1

Andres A. Caro and Arthur I. Cederbaum
Molecular Pharmacology October 1, 2001, 60 (4) 742-752;
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