Selective hepatobiliary transport defect for organic anions and neutral steroids in mutant rats with hereditary‐conjugated hyperbilirubinemia
Selective hepatobiliary transport defect for organic anions and neutral steroids in mutant rats with hereditary‐conjugated hyperbilirubinemia
复制标题
遗传性结合高胆红素血症突变大鼠有机阴离子和中性类固醇的选择性肝胆转运缺陷
作者：
P. Jansen;G. Groothuis;W. Peters;Dirk F. M. Meijer
用肝排泄功能异常的突变大鼠(TM大鼠)研究二溴磺基邻苯二甲酸、哇巴因、三丁基甲基铵、胆酸盐和牛磺胆酸盐的胆汁转运。在整个动物中，由于从肝脏到胆汁的排泄严重受损，二溴磺胺和哇巴因的清除量分别减少到正常的7%和37%。这些药物的初始摄取率受影响相对较小。在离体灌流肝制剂中，二溴磺化邻苯二甲酸保留在肝脏和灌流液中，胆汁在60min内的回收率由正常对照组的75%降至1.5%。胆酸盐、牛磺胆酸盐和季铵盐阳离子[14C]三丁基甲基铵的胆汁排泄不受影响。这些结果为TM大鼠体内有机阴离子和中性类固醇转运的选择性缺陷提供了证据，并证实了有机阴离子、中性类固醇、胆汁酸和阳离子在肝胆排泄中存在多种途径。整体动物和隔离灌流肝脏的胆汁流量分别减少到正常的50%和30%。这表明，有机阴离子和中性类固醇排泄系统的正常功能对维持正常的胆汁流量很重要。
Mutant rats (TM rats) with abnormal hepatic excretory function were used to study biliary transport of dibromosulfophthalein, ouabain, tributylmethyl ammonium, cholate and taurocholate. In whole animals, dibromosulfophthalein and ouabain clearance is reduced to 7 and 37% of normal, respectively, due to severely impaired excretion from liver to bile. Initial uptake rates of these agents are relatively little affected. In the isolated perfused liver preparation, dibromosulfophthalein is retained within liver and perfusion medium, and the 60‐min recovery on bile is reduced to 1.5 vs 75% in normal controls. Biliary excretion of cholate, taurocholate and the quaternary ammonium cation, [14C]tributylmethyl ammonium, is not impaired. These results provide evidence for a selective defect of organic anion and neutral steroid transport in TM rats and confirm that multiple pathways exist for the hepatobiliary excretion of organic anions, neutral steroids, bile acids and cations. Bile flow in whole animals and in the isolated perfused liver is reduced to 50 and 30% of normal, respectively. This suggests that a normal function of the excretory systems for organic anions and neutral steroids is important for the maintenance of normal bile flow.