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Selective hepatobiliary transport of nordeoxycholate side chain conjugates in mutant rats with a canalicular transport defect
Author(s) -
Elferink Ronald P. J. Oude,
de Haan Jan,
Lambert Karel J.,
Hagey Lee R.,
Hofmann Alan F.,
Jansen Peter L. M.
Publication year - 1989
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840090612
Subject(s) - mutant , chemistry , conjugate , side chain , biochemistry , biophysics , microbiology and biotechnology , biology , gene , organic chemistry , mathematical analysis , mathematics , polymer
Canalicular transport of bilirubin diglucuronide, dibromosulfophthalein and several glutathione conjugates is deficient in mutant TR − rats. In contrast, transport of cholyltaurine (taurocholate), a conjugated bile acid, is normal. Previous studies using normal rats have shown that C 23 nor‐dihydroxy bile acids are conjugated with sulfate or glucuronide during hepatic transport in contrast to the natural C 24 bile acids, which are amidated with glycine or taurine. Studies were performed to test the hypothesis that (a) in the TR − rat, 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 23 ‐ 14 C]Nordeoxycholate was administered intravenously to bile fistula rats (TR − and 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 23 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 23‐taurine 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 mutant rats. Canalicular secretion of unconjugated, amidated or esterified nordeoxycholate is mediated via another pathway, probably the “bile acid transport system.” It is speculated that the “bile acid transport system” transports large organic anions with one (or more) negative charges on one side chain (“unipolar anions”), whereas the “bilirubin transport system” transports large organic anions with at least two separate negative side chains tentatively termed “multipolar anions,” which include the 3‐sulfates and 3‐glucuronides of bile acids.