Selective hepatobiliary transport defect for organic anions and neutral steroids in mutant rats with hereditary-conjugated hyperbilirubinemia
✍ Scribed by Peter L. M. Jansen; Geny M. M. Groothuis; Wilbert H. M. Peters; Dirk F. M. Meijer
- Book ID
- 102848338
- Publisher
- John Wiley and Sons
- Year
- 1987
- Tongue
- English
- Weight
- 571 KB
- Volume
- 7
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Mutant rats (TM rats) with abnormal hepatic excretory function were used to study biliary traneport of dieromoeulfophthalein, ouabain, tributylmethyl ammonium, cholate and taurocholate. In whole animals, dib r o d o p h t h a l e i n and ouabain clearance is reduced to 7 and 37% of normal, respectively, due to severely impaired excretion from liver to bile. Initial uptake rptee of theee agents are relatively little affected. In the ieolrted pertrrsed liver preparation, dibrommlfophthaleh is retained within liver and perfusion medium, and the 60-min recovery on bile is reduced to 1.6 vs 76% in normal controls. Biliary excretion of cholate, taurocholate and the quaternary ammonium cation, [l'CItributylmetbyl ammonium, is not impaired. These results provide evidemce 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 amd &M. Bile flow in whole animals and in the isolated perfwed liver is reduced to 60 and 30% of normal, mqmctively. This suggests that a normal function of the excretory Byeterns for organic anions and neutral steroids is important for the maintenance of normal bile flow.
Hepatic organic ion transport is a complex process. Before ions can be excreted into bile, they have to be delivered to the liver and taken up into the hepatocyte. Sodium-dependent hepatic uptake of alanine and bile acids, and sodium-independent uptake of bilirubin and tetrabromosulfophthalein (1-9) are probably carrier-mediated processes. Several candidate carrier proteins have been proposed (10)(11)(12). Once inside the hepatocyte, most compounds are first metabolized and subsequently delivered to the canalicular membrane for transport into the bile. Pharmacokinetic studies indicate that canalicular