Distribution of heme oxygenase isoforms in rat liver. Topographic basis for carbon monoxide-mediated microvascular relaxation

J Clin Invest. 1998 Feb 1;101(3):604-12. doi: 10.1172/JCI1324.


Carbon monoxide (CO) derived from heme oxygenase has recently been shown to play a role in controlling hepatobiliary function, but intrahepatic distribution of the enzyme is unknown. We examined distribution of two kinds of the heme oxygenase isoforms (HO-1 and HO-2) in rat liver immunohistochemically using monoclonal antibodies. The results showed that distribution of the two isoforms had distinct topographic patterns: HO-1, an inducible isoform, was observed only in Kupffer cells, while HO-2, a constitutive form, distributed to parenchymal cells, but not to Kupffer cells. Both isoforms were undetectable in hepatic stellate cells and sinusoidal endothelial cells. Of the two isoforms, HO-2 in the parenchymal cell rather than HO-1 in the Kupffer cell, appears to play a major role in regulation of microvascular tone. In the perfused liver, administration of HbO2, a CO-trapping reagent that can diffuse across the fenestrated endothelium into the space of Disse, elicited a marked sinusoidal constriction, while administration of a liposome-encapsulated Hb that cannot enter the space had no effect on the microvascular tone. These results suggest that CO evolved by HO-2 in the parenchymal cells, and, released to the extrasinusoidal space, served as the physiological relaxant for hepatic sinusoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / metabolism
  • Carbon Monoxide / metabolism
  • Cells, Cultured
  • Female
  • Heme Oxygenase (Decyclizing) / biosynthesis*
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase-1
  • Hemoglobins / administration & dosage
  • Isoenzymes / biosynthesis*
  • Isoenzymes / genetics
  • Liposomes
  • Liver / cytology
  • Liver / metabolism*
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred BALB C
  • Rats
  • Rats, Wistar
  • Vasoconstrictor Agents


  • Antibodies, Monoclonal
  • Hemoglobins
  • Isoenzymes
  • Liposomes
  • Membrane Proteins
  • Vasoconstrictor Agents
  • Carbon Monoxide
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • heme oxygenase-2