Toxicological Sciences, Vol 48, 264-274, Copyright © 1999 by Society of Toxicology
HA Boulares, C Giardina, CL Navarro, EA Khairallah and SD Cohen
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.
ARTICLES
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
Department of Molecular and Cell Biology, University of Connecticut, Storrs 06269, USA.
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