Modulation of serum growth factor signal transduction in Hepa 1-6 cells by acetaminophen: an inhibition of c-myc expression, NF-kappaB activation, and Raf-1 kinase activity.
Acetaminophen (APAP) is a widely used analgesic and antipyretic that can lead to severe liver damage when taken at excessive doses. APAP toxicity results when cytochrome P450-generated APAP metabolites trigger an oxidative stress and covalently modify target proteins. APAP has also been reported to inhibit cells from completing S-phase through a cytochrome P450-independent mechanism, raising the possibility that APAP may directly suppress liver regeneration and repair. Here we show that APAP also inhibits entrance of Hepa 1-6 cells into the cell cycle by blocking a number of events associated with the G0-G1 transition. We have found that APAP inhibits serum growth factor activation of c-myc expression, NF-kappaB DNA binding, and Raf kinase. Therefore, the ability of APAP to inhibit passage of cells through both G1 and S phases might interfere with organ regeneration and thus exacerbate acute liver damage caused by APAP.
Boulares
H A
HA
Department of Molecular and Cell Biology, University of Connecticut, Storrs 06269, USA.
Giardina
C
C
Navarro
C L
CL
Khairallah
E A
EA
Cohen
S D
SD
D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D018736:DNA Adducts / Q000096:biosynthesis; D016259:Genes, myc / Q000187:drug effects*; D006133:Growth Substances / Q000097:blood / Q000235:genetics*; D006801:Humans; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D018712:Analgesics, Non-Narcotic; D018736:DNA Adducts; D006133:Growth Substances; D016328:NF-kappa B; D000082:Acetaminophen; D019908:Proto-Oncogene Proteins c-raf