Acetaminophen inhibits NF-κB activation by interfering with the oxidant signal in murine hepa 1-6 cells

Abstract

A toxic dose of acetaminophen (APAP) reduces the activity of NF-κB in mouse liver. NF-κB 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-κB 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-κB 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-κB activation and IκBα degradation, and APAP was able to block both of these events. The APAP inhibition of NF-κB 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-κB and oxidant-based growth factor signal transduction in APAP toxicity is discussed.