Toxicological Sciences 55, 370-375 (2000)
Copyright © 2000 by the Society of Toxicology
Acetaminophen Inhibits NF-
B Activation by Interfering with the Oxidant Signal in Murine Hepa 1-6 Cells
,3
* Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut 06269; and
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269
A toxic dose of acetaminophen (APAP) reduces the activity of NF-
B in mouse liver. NF-B inactivation may be important for APAP toxicity, as this transcription factor can play a central role in maintaining hepatic viability. We recently reported that APAP likewise inhibits serum growth factor activation of NF-B in a mouse hepatoma cell line (Hepa 1-6 cells). Here we present evidence that APAP's antioxidant activity may be involved in this NF-B inhibition in Hepa 1-6 cells. Like the antioxidants N-acetylcysteine (NAC) and pyrrolidinedithiocarbamate (PDTC), APAP was found to suppress the H2O2-induced oxidation of an intracellular reactive oxygen species probe (dihydrodichlorofluorescein) in Hepa 1-6 cells. Treatment of Hepa 1-6 cells with H2O2 was sufficient for NF-B activation and IB
degradation, and APAP was able to block both of these events. The APAP inhibition of NF-B activation by serum growth factors may also be due to APAP's antioxidant activity, as the antioxidants NAC and PDTC likewise inhibit this activation. The potential role of NF-B and oxidant-based growth factor signal transduction in APAP toxicity is discussed.
Key Words: acetaminophen; NF-B; IB; Hepa 1-6; hepatotoxicity; reactive oxygen; antioxidants.
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