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Acetaminophen Induces Apoptosis of C6 Glioma Cells by Activating the c-Jun NH2-Terminal Protein Kinase-Related Cell Death Pathway
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 apoptosi...
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Published in: | Molecular pharmacology 2001-10, Vol.60 (4), p.847 |
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Main Authors: | , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | 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 LysâArg 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 of CYP2E1 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. |
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ISSN: | 0026-895X 1521-0111 |