Carbon monoxide from heme catabolism protects against hepatobiliary dysfunction in endotoxin-treated rat liver.
OBJECTIVE
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.
First Department of Surgery, Nagoya University School of Medicine, Nagoya, Japan.
T
T
Kyokane
S
S
Norimizu
H
H
Taniai
T
T
Yamaguchi
S
S
Takeoka
E
E
Tsuchida
M
M
Naito
Y
Y
Nimura
Y
Y
Ishimura
M
M
Suematsu
D000818:Animals; D001646:Bile / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008706:Methemoglobin / Q000378:metabolism / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010108:Oxyhemoglobins / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012769:Shock / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism; D065227:Transfusion Reaction; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
D008070:Lipopolysaccharides; D010108:Oxyhemoglobins; D009569:Nitric Oxide; D006418:Heme; D002248:Carbon Monoxide; D008706:Methemoglobin; D003577:Cytochrome P-450 Enzyme System