title: Carbon monoxide may enhance bile secretion by increasing glutathione excretion and Mrp2 expression in rats.
abstract: BACKGROUND
  Nitric oxide (NO) donors have been reported to induce choleresis via an increased excretion of glutathione. The effects of another gas molecule, carbon monoxide (CO), on bile formation are, however, inconsistent among previous reports. We investigated the sequential changes of bile output and the biliary contents in rats with or without CO supplementation to elucidate the mechanism of CO on bile excretion.
  
  
  METHODS
  Dichloromethane (DCM) was gastrically fed to male Sprague-Dawley rats to yield CO by liver biotransformation. The rats were divided into DCM-treated (n = 7), DCM plus L-NAME-treated (n = 6), and corn oil-treated-(n = 8) groups. Bile samples were collected hourly to examine the flow rate and bile content. Serum levels of nitrite and nitrate 4 hours after DCM supplementation with or without NO synthase (NOS) inhibition were measured by capillary electrophoresis. The expression of hepatic inducible NOS was evaluated by Western blotting 6 hours after DCM administration.
  
  
  RESULTS
  Levels of carboxyhemoglobin rose to around 10% at 4 hours after DCM supplementation and were maintained until the end of the experiments. Bile flow increased after DCM supplementation and was associated with a concomitant increase of biliary glutathione and higher hepatic multidrug resistance-associated protein 2 (Mrp2) expression. Hepatic inducible NOS expression and serum nitrate/nitrite levels were also increased. Treatment with an NOS inhibitor (L-NAME) abolished the CO-induced glutathione excretion and choleresis, but not Mrp2 expression.
  
  
  CONCLUSIONS
  The present study demonstrated that CO enhanced biliary output in conjunction with NO by increasing the biliary excretion of glutathione. The increment in biliary glutathione was associated with an increased expression of hepatic Mrp2.
authors.affiliation: Department of Internal Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Chiung-Yu
authors.initials: CY
authors.lastname: Chen
authors.forename: Chi-Ya
authors.initials: CY
authors.lastname: Kao
authors.forename: Po-Ju
authors.initials: PJ
authors.lastname: Lin
authors.forename: Shu-Chu
authors.initials: SC
authors.lastname: Shiesh
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002263:Carboxyhemoglobin / Q000032:analysis; D005978:Glutathione / Q000378:metabolism*; D008297:Male; D008752:Methylene Chloride / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D009569:Nitric Oxide; D008752:Methylene Chloride; D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D052247:Nitric Oxide Synthase Type II; D005978:Glutathione