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A more recent version of this article appeared on September 1, 2004

Papers In Press, published online ahead of print June 1, 2004
J. Lipid Res., doi:10.1194/jlr.M400157-JLR200
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Submitted on April 23, 2004
Revised on May 28, 2004
Accepted on May 29, 2004

Bio-conversion of 3b-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat brain enzyme systems

Nariyasu Mano, Yoshiaki Sato, Masanori Nagata, Takaaki Goto, and Junichi Goto

Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574

Corresponding Author: jun-goto{at}mail.pharm.tohoku.ac.jp

We have previously demonstrated that the rat brain contains three unconjugated bile acids, and chenodeoxycholic acid is the most abundantly presented in a tight protein binding form (Mano, N. et al. 2004. J. Lipid Res. 45: 295-300). The ratio of chenodeoxycholic acid to the other acids in rat brain tissue was significantly higher than the ratio in the peripheral blood, indicating a contribution from either a specific uptake mechanism or a biosynthetic pathway for chenodeoxycholic acid in rat brain. In this study, we have demonstrated the existence of an enzymatic activity which converts 3b-hydroxy-5-cholenoic acid into chenodeoxycholic acid in rat brain tissue by utilizing liquid chromatography/electrospray ionization mass spectrometric analysis. To distinguish marked compounds from endogenous related compounds, 18O-labeled 3b-hydroxy-5-cholenoic acid, 3b,7a-dihydroxy-5-cholenoic acid, and 7a-hydroxy-3-oxo-4-cholenoic acid were synthesized as substrates for in vitro incubation studies. The results clearly suggest that 3b-hydroxy-5-cholenoic acid was converted to 3b,7a-dihydroxy-5-cholenoic acid by microsomal enzymes in an NADPH dependent manner. The 7a-hydroxy-3-oxo-4-cholenoic acid was produced from 3b,7a-dihydroxy-5-cholenoic acid by the action of a microsomal enzyme preparation in an NAD+ dependent manner, and D4-3-oxo acid was converted to chenodeoxycholic acid by rat brain cytosolic enzymes in an NADPH dependent manner. These findings indicate the presence of an enzymatic activity that converts 3b-hydroxy-5-cholenoic acid into chenodeoxycholic acid in rat brain tissue. Furthermore, this synthetic pathway for chenodeoxycholic acid may relate to the function of 24S-hydroxycholesterol, which plays an important role in cholesterol homeostasis in the body.


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