Carbon monoxide from heme catabolism protects against hepatobiliary dysfunction in endotoxin-treated rat liver

Takanori Kyokane, Shinji Norimizu, Hisashi Taniai, Tokio Yamaguchi, Shinji Takeoka, Eishun Tsuchida, Makoto Naito, Yuji Nimura, Yuzuru Ishimura, Makoto Suematsu

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Abstract

Background & Aims: Liver is a major organ for heme detoxification under disease conditions, but its self-protective mechanisms against the toxicity are unknown. This study aimed to examine roles of carbon monoxide (CO), the gaseous product of heme oxygenase (HO), in ameliorating hepatobiliary dysfunction during catabolism of heme molecules in endotoxemic livers. Methods: Vascular resistance and biliary flux of bilirubin-IXα, an index of HO-derived CO generation, were monitored in perfused livers of endotoxemic rats. Livers were perfused with HbO2, which captures nitric oxide (NO) and CO, or metHb, a reagent trapping NO but not CO. Results: In endotoxin-pretreated livers where inducible NO synthase and HO-1 overproduced NO and CO, HbO2 caused marked vasoconstriction and cholestasis. These changes were not reproduced by the NO synthase inhibitor aminoguanidine alone, but by coadministration of zinc protoporphyrin-IX, an HO inhibitor. CO supplementation attenuated the events caused by aminoguanidine plus zinc protoporphyrin-IX, suggesting that simultaneous elimination of these vasorelaxing gases accounts for a mechanism for HbO2-induced changes. This concept was supported by observation that metHb did not cause any cholestasis; the reagent captures NO but triggers CO overproduction through rapid degradation of the heme by HO-1. Conclusions: These results suggest protective roles of CO against hepatobiliary dysfunction caused by heme overloading under stress conditions.

Original languageEnglish
Pages (from-to)1227-1240
Number of pages14
JournalGastroenterology
Volume120
Issue number5
DOIs
Publication statusPublished - 2001 Jan 1

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ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Kyokane, T., Norimizu, S., Taniai, H., Yamaguchi, T., Takeoka, S., Tsuchida, E., Naito, M., Nimura, Y., Ishimura, Y., & Suematsu, M. (2001). Carbon monoxide from heme catabolism protects against hepatobiliary dysfunction in endotoxin-treated rat liver. Gastroenterology, 120(5), 1227-1240. https://doi.org/10.1053/gast.2001.23249