Carbon monoxide mediates heme oxygenase 1 induction via Nrf2 activation in hepatoma cells

Biochem Biophys Res Commun. 2006 May 12;343(3):965-72. doi: 10.1016/j.bbrc.2006.03.058. Epub 2006 Mar 29.


Carbon monoxide (CO) and nitric oxide (NO) are two gas molecules which have cytoprotective functions against oxidative stress and inflammatory responses in many cell types. Currently, it is known that NO produced by nitric oxide synthase (NOS) induces heme oxygenase 1 (HO1) expression and CO produced by the HO1 inhibits inducible NOS expression. Here, we first show CO-mediated HO1 induction and its possible mechanism in human hepatocytes. Exposure of HepG2 cells or primary hepatocytes to CO resulted in dramatic induction of HO1 in dose- and time-dependent manner. The CO-mediated HO1 induction was abolished by MAP kinase inhibitors (MAPKs) but not affected by inhibitors of PI3 kinase or NF-kappaB. In addition, CO induced the nuclear translocation and accumulation of Nrf2, which suppressed by MAPKs inhibitors. Taken together, we suggest that CO induces Nrf2 activation via MAPKs signaling pathways, thereby resulting in HO1 expression in HepG2 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Carbon Monoxide / pharmacology*
  • Carcinoma, Hepatocellular
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Gene Expression Regulation, Enzymologic*
  • Heme Oxygenase-1 / biosynthesis
  • Heme Oxygenase-1 / genetics*
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology*
  • Hepatocytes / metabolism
  • Humans
  • Liver Neoplasms
  • MAP Kinase Signaling System
  • NF-E2-Related Factor 2 / metabolism*
  • Promoter Regions, Genetic
  • Rats
  • Response Elements
  • Transcriptional Activation*
  • Up-Regulation


  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Carbon Monoxide
  • HMOX1 protein, human
  • Heme Oxygenase-1