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Vol. 60, Issue 4, 847-856, October 2001
Laboratory of Membrane Biochemistry and Biophysics, National
Institute on Alcohol Abuse and Alcoholism, National Institutes of
Health, Rockville, Maryland
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 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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