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Effect of side chain length on bile acid conjugation: Glucuronidation, sulfation and coenzyme a formation of nor‐bile acids and their natural C 24 homologs by human and rat liver fractions
Author(s) -
Kirkpatrick Robert B.,
Green Mitchell D.,
Hagey Lee R.,
Hofmann Alan F.,
Tephly Thomas R.
Publication year - 1988
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.1840080227
Subject(s) - glucuronidation , sulfation , chemistry , biochemistry , bile acid , cyp8b1 , microsome , g protein coupled bile acid receptor , enzyme
The effect of side chain length on bile acid conjugation by human and rat liver fractions was examined. The rate of conjugation with glucuronic acid, sulfate and coenzyme A of several natural (C 24 ) bile acids was compared with that of their corresponding nor‐bile acids. The rate of coenzyme A ester formation by nor‐bile acids was much lower than that of the natural bile acids. In human liver microsomes, the rate of coenzyme A formation was <8% of the rate for the corresponding C 24 bile acid. Rat liver microsomes formed the coenzyme A ester of nor‐bile acids <20% of the rate of their corresponding C 24 homologs. Glucuronidation rates were greater than sulfation rates in both species. With human liver microsomes, nor‐bile acids were glucuronidated more rapidly than their corresponding C 24 homologs, whereas with rat liver microsomes the reverse was true. Purified 3α‐OH androgen UDP‐glucuronyltransferase catalyzed the glucuronidation of both nor‐bile acids and bile acids. Human liver cytosol sulfated nor‐bile acids more slowly than the corresponding bile acids. Rat liver cytosol, however, sulfated nor‐bile acids more rapidly than the corresponding bile acids. The highest rate was seen with lithocholylglycine. The results indicate that the novel biotransformation of nor‐bile acids seen in vivo —sulfation and glucuronidation rather than amidation—is most likely explained as a consequent of defective amidation, to which the rate of coenzyme A formation contributes. Thus, side chain and nuclear structures as well as species differences in conjugating enzyme activity are determinants of the pattern of bile acid biotransformation by the mammalian liver.