Acetaminophen inhibits NF-kappaB activation by interfering with the oxidant signal in murine Hepa 1-6 cells.
A toxic dose of acetaminophen (APAP) reduces the activity of NF-kappaB in mouse liver. NF-kappaB 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-kappaB 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-kappaB inhibition in Hepa 1-6 cells. Like the antioxidants N-acetylcysteine (NAC) and pyrrolidinedithiocarbamate (PDTC), APAP was found to suppress the H(2)O(2)-induced oxidation of an intracellular reactive oxygen species probe (dihydrodichlorofluorescein) in Hepa 1-6 cells. Treatment of Hepa 1-6 cells with H(2)O(2) was sufficient for NF-kappaB activation and IkappaBalpha degradation, and APAP was able to block both of these events. The APAP inhibition of NF-kappaB 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-kappaB and oxidant-based growth factor signal transduction in APAP toxicity is discussed.
Boulares
A H
AH
Department of Molecular and Cell Biology, University of Connecticut, Storrs 06269, USA.
Giardina
C
C
Inan
M S
MS
Khairallah
E A
EA
Cohen
S D
SD
D000082:Acetaminophen / Q000494:pharmacology*; D000111:Acetylcysteine / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D015342:DNA Probes / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D005452:Fluoresceins / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020672:I-kappa B Proteins; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013859:Thiocarbamates / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C109098:2,7-dihydrodichlorofluorescein diacetate; D018712:Analgesics, Non-Narcotic; D000975:Antioxidants; D015342:DNA Probes; D004268:DNA-Binding Proteins; D005452:Fluoresceins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011759:Pyrrolidines; D013859:Thiocarbamates; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid; D000082:Acetaminophen; D006861:Hydrogen Peroxide; D000111:Acetylcysteine