Carbon monoxide from heme catabolism protects against hepatobiliary dysfunction in endotoxin-treated rat liver.
BACKGROUND AND 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-IXalpha, an index of HO-derived CO generation, were monitored in perfused livers of endotoxemic rats. Livers were perfused with HbO(2), 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, HbO(2) 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 HbO(2)-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.[1]References
- Carbon monoxide from heme catabolism protects against hepatobiliary dysfunction in endotoxin-treated rat liver. Kyokane, T., Norimizu, S., Taniai, H., Yamaguchi, T., Takeoka, S., Tsuchida, E., Naito, M., Nimura, Y., Ishimura, Y., Suematsu, M. Gastroenterology (2001) [Pubmed]
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