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Molecular Pharmacology

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Research ArticleArticle

Acetaminophen Induces Apoptosis of C6 Glioma Cells by Activating the c-Jun NH2-Terminal Protein Kinase-Related Cell Death Pathway

Myung-Ae Bae, Jae-Eun Pie and Byoung J. Song
Molecular Pharmacology October 2001, 60 (4) 847-856;
Myung-Ae Bae
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Jae-Eun Pie
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Byoung J. Song
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Abstract

Acetaminophen (AAP), a widely used analgesic drug, can damage various organs when taken in large doses. In this study, we investigate whether AAP causes cell damage by altering the early signaling pathways associated with cell death and survival. AAP caused time- and concentration-dependent apoptosis and DNA fragmentation of C6 glioma cells used as a model. AAP activated c-Jun N-terminal protein kinase (JNK) by 5.3-fold within 15 min. The elevated JNK activity persisted for up to 4 h before it returned to the basal level at 8 h. In contrast, activities of other mitogen-activated protein (MAP) kinases and the level of Akt phosphorylation in the cell survival pathway remained unchanged throughout the treatment. Wortmannin, an inhibitor of phosphatidylinositol-3 kinase, or SB203580, an inhibitor of p38 MAP kinase, did not reduce AAP-induced toxicity, indicating that these enzymes do not play a major role in cell toxicity. AAP-induced apoptosis was preceded by the sequential elevation of the pro-apoptotic Bax protein, cytochrome c release, and caspase-3 activity. Treatment with caspase inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (Z-DEVD-FMK) significantly reduced AAP-induced caspase-3 activation and cytotoxicity. Transfection of cDNA for the dominant-negative mutant JNK-KR or stress-activated protein kinase kinase-1 Lys→Arg mutant (SEK1-KR), an immediate upstream kinase of JNK, significantly reduced AAP-induced JNK activation and cell death rate. The noncytotoxic analog of AAP, 3-hydroxyacetanilide, neither increased JNK activity nor caused apoptosis. Pretreatment with YH439, an inhibitor ofCYP2E1 gene transcription, markedly reduced CYP2E1 mRNA, protein content, and activity, as well as the rate of AAP-induced JNK activation and cell death. These data indicate that AAP can cause cell damage by activating the JNK-related cell death pathway, providing a new mechanism for AAP-induced cytotoxicity.

Footnotes

  • ↵1 Current address: Department of Food Science and Nutrition, An-Yang University, An-Yang, Korea.

  • Abbreviations:
    AAP
    acetaminophen
    NAPQI
    N-acetyl-p-benzoquinoneimine
    MAP
    mitogen-activated protein
    JNK
    c-Jun NH2-terminal protein kinase
    ERK
    extracellular signal-regulated protein kinase
    PI-3K
    phosphatidylinositol-3 kinase
    P450
    cytochrome P450
    DAPI
    4,6-diamidino-2-phenylindole
    DMSO
    dimethyl sulfoxide
    YH439
    isopropyl 2-(1,3-dithioetane-2-ylidene)-2-[N-(4-methylthiazol-2-yl) carbamoyl]acetate
    Z-DEVD-FMK
    benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone
    Ac-DEVD-AMC
    acetyl-Asp-Glu-Val-Asp-amino-4-methylcoumarin
    LDH
    lactate dehydrogenase
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    wt
    wild type
    SEK1
    stress-activated protein kinase kinase 1
    SEK1-KR
    stress activated protein kinase kinase -1 Lys→Arg mutant
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    bp
    base pair
    MEKK1
    mitogen-activated protein kinase kinase kinase 1
    NDMA
    N-nitrosodimethylamine
    • Received March 6, 2001.
    • Accepted July 5, 2001.
  • U.S. Government
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Molecular Pharmacology: 60 (4)
Molecular Pharmacology
Vol. 60, Issue 4
1 Oct 2001
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Research ArticleArticle

Acetaminophen Induces Apoptosis of C6 Glioma Cells by Activating the c-Jun NH2-Terminal Protein Kinase-Related Cell Death Pathway

Myung-Ae Bae, Jae-Eun Pie and Byoung J. Song
Molecular Pharmacology October 1, 2001, 60 (4) 847-856;

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Research ArticleArticle

Acetaminophen Induces Apoptosis of C6 Glioma Cells by Activating the c-Jun NH2-Terminal Protein Kinase-Related Cell Death Pathway

Myung-Ae Bae, Jae-Eun Pie and Byoung J. Song
Molecular Pharmacology October 1, 2001, 60 (4) 847-856;
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