Selective hepatobiliary transport of nordeoxycholate side chain conjugates in mutant rats with a canalicular transport defect

✍ Scribed by Ronald P. J. Oude Elferink; Jan de Haan; Karel J. Lambert; Lee R. Hagey; Alan F. Hofmann; Peter L. M. Jansen

• Book ID: 102851608
• Publisher: John Wiley and Sons
• Year: 1989
• Tongue: English
• Weight: 627 KB
• Volume: 9
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.1840090612

✦ Synopsis

Canalicular transport of bilirubin diglucuronide, dibromosulfophthalein and several glutathione conjugates is deficient in mutant TRrats. In contrast, transport of cholyltaurine (taurocholate), a conjugated bile acid, is normal. Previous studies using normal rats have shown that C,, nor-dihydroxy bile acids are conjugated with sulfate or glucuronide during hepatic transport in contrast to the natural C,, bile acids, which are amidated with glycine or taurine. Studies were performed to test the hypothesis that (a) in the TRrat, nordeoxycholate would be conjugated with glucuronate or sulfate just as in the normal rat, and (b) that such conjugates would have defective biliary secretion. [C~:l-'"C]Nordeoxycholate was administered intravenously to bile fistula rats (TRand normal), and the biliary recovery of metabolites was assessed by chromatography and mass spectrometry.

In both groups of rats, the major biotransformation product of nordeoxycholate was the side chain (23-ester) glucuronide. Conjugation on the nucleus with sulfate and glucuronide at the 3-position (ethereal linkage) also occurred, as well as amidation at the C,, carboxylic acid group. In the mutant rats, biliary secretion of the 3- sulfate and 3-glucuronide conjugates was less than 10% and 1%. respectively, of that of normal rats, whereas biliary secretion of the 23-ester glucuronide and the 23taurine amidate, as well as unchanged nordeoxycholate, was not decreased. Canalicular secretion of nor-bile acid 3-ether glucuronides and 3-sulfates appears to involve the "bilirubin transport system," which is deficient in