Carbon monoxide stimulates mrp2-dependent excretion of bilirubin-IXα into bile in the perfused rat liver
Carbon monoxide stimulates mrp2-dependent excretion of bilirubin-IXα into bile in the perfused rat liver
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DOI：
10.1089/152308603768295195
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发表时间：
2003-08-01
影响因子：
6.6
通讯作者：
Suematsu, M
中科院分区：
文献类型：
--
作者：
Norimizu, S;Kudo, A;Suematsu, M
虽然一氧化碳(CO)已被报道对肝胆功能障碍有保护作用，但其作用机制仍不清楚。本研究旨在研究生理相关浓度的CO对胆汁排泄的作用。在大鼠肝脏灌流模型上，观察了门静脉注射CO对胆汁产量和胆汁成分的影响。在喂饲大鼠的肝脏中，CO以剂量依赖的方式双向调节胆汁排出量，经门静脉注射CO 4mumol/L时，胆汁排出量增加10%。在这种情况下，CO增加了细胞旁连接的通透性，从而减少了胆汁盐的排泄。胆汁中胆红素-IXα和谷胱甘肽的排泄量显著增加，4-莫尔/L CO引起的胆汁排泄与胆汁中胆红素-IXa和谷胱甘肽的排泄显著增加相吻合。CO诱导的胆汁排泄不依赖于环状GMP，与K+和HCO3-排泄增加相一致，并可被四乙基铵消除，提示气体对钾通道有刺激作用。共介导的胆汁排泄和有机阴离子排泄增加似乎是由mrp2介导的，因为卫材高胆红素血症大鼠在基因上缺乏转运体，在CO注射后不表现出胆汁排泄。这些结果表明，CO通过钾通道机制刺激mrp2依赖的胆红素-IXα的分泌，作为血红素加氧酶反应的合作者，促进肝脏的血红素解毒。
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 mumol/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 mumol/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 HCO3-, 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.