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Specificity of the hepatocyte Na + ‐dependent taurocholate transporter: Influence of side chain length and charge
Author(s) -
Hardison William G. M.,
Heasley Victor L.,
Shellhamer Dale F.
Publication year - 1991
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.1840130111
Subject(s) - side chain , chemistry , sterol , biophysics , carbon chain , moiety , transporter , nucleus , stereochemistry , bile acid , biochemistry , cholesterol , biology , organic chemistry , microbiology and biotechnology , gene , polymer
Trihydroxy bile acids with differing nonsterol chain length and charge were synthesized to define the effect of these parameters on the ability to competitively inhibit the Na + ‐dependent uptake of 14 C taurocholate into isolated rat hepatocytes. Compounds with long side chains (≥ 0.8 nm) beyond carbon‐17 of the sterol nucleus and carrying a negative charge or no charge were potent inhibitors. Introduction of a positive charge into the side chain weakened inhibition. When the length of the chain beyond carbon‐17 fell below about 0.7 nm, charge still influenced inhibitory potency, but the effect was reversed and positively‐charged chains yielded slightly greater inhibition than negatively‐charged chains. From these results one may postulate a positively‐charged cell surface domain extending outward from a point about 0.7 nm from the sterol nucleus receptor region. Up to about 0.7 nm from the sterol nucleus receptor region one might postulate a negative cell surface charge to account for the weaker inhibitory potency of compounds with short negatively‐charged chains. Nonetheless, a short chain, regardless of charge, weakened inhibition, suggesting that a long negatively‐charged side chain is necessary to orient the sterol moiety for optimal receptor fit. These data confirm that the Na + ‐dependent taurocholate transport site is sensitive to alterations of side chain charge and length and emphasize the importance of structure when designing bile acid analogs to probe taurocholate transport mechanisms. (H EPATOLOGY 1991;13:68–72).