Carbon monoxide stimulates mrp2-dependent excretion of bilirubin-IXalpha into bile in the perfused rat liver.
Although carbon monoxide (CO) has been reported to protect against hepatobiliary dysfunction, mechanisms for its actions remain unknown. This study aimed to examine actions of physiologically relevant concentrations of CO on biliary excretion. The effects of transportal administration of CO on bile output and constituents were examined in perfused rat livers. In livers of fed rats, CO regulated bile output biphasically in a dose-dependent manner; transportal administration of CO at 4 micro mol/L stimulated bile output by 10%. Under these circumstances, CO increased paracellular junctional permeability and consequently decreased biliary excretion of bile salts. Choleresis elicited by 4 micro mol/L CO coincided with significant increases in biliary excretion of bilirubin-IXalpha and glutathione. The CO-induced choleresis occurred independently of cyclic GMP, coincided with elevated excretion of K(+) and HCO(3)(-), and was abolished by tetraethylammonium, suggesting stimulatory effects of the gas on potassium channels. CO-mediated choleresis and increased excretion of organic anions appeared to be mediated by mrp2, because Eisai hyperbilirubinemia rats, which genetically lack the transporter, did not exhibit choleresis upon the CO administration. These results suggest that CO stimulates mrp2-dependent excretion of bilirubin-IXalpha through mechanisms involving potassium channels, serving as a cooperator standing behind the heme oxygenase reaction to facilitate hepatic heme detoxification.
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism*; D005452:Fluoresceins / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006735:Horseradish Peroxidase / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D019789:Tetraethylammonium / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D001639:Bicarbonates; D002352:Carrier Proteins; D005452:Fluoresceins; D015221:Potassium Channels; D019789:Tetraethylammonium; C045132:4-carboxyfluorescein; D002248:Carbon Monoxide; D006735:Horseradish Peroxidase; D005978:Glutathione; D001663:Bilirubin; D011188:Potassium