Modulation of serum growth factor signal transduction in Hepa 1-6 cells byacetaminophen: An inhibition of c-myc expression, NF-kappa B activation, and Raf-1 kinase activity

Acetaminophen (APAP) is a widely used analgesic and antipyretic that can le ad to severe liver damage when taken at excessive doses. APAP toxicity resu lts when cytochrome P450-generated APAP metabolites trigger an oxidative st ress and covalently modify target proteins. APAP has also been reported to inhibit cells from completing S-phase through a cytochrome P350-independent mechanism, raising the possibility that APAP may directly suppress liver r egeneration and repair. Here we show that APAP also inhibits entrance of He pa 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 fa ctor activation of c-myc expression, NF-kappa B DNA binding, and Raf kinase . Therefore, the ability of APAP to inhibit passage of cells through both G 1 and S phases might interfere with organ regeneration and thus exacerbate acute liver damage caused by APAP.