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Journal of Lipid Research, Vol. 45, 1741-1748, September 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Bioconversion of 3ß-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat brain enzyme systems

Nariyasu Mano^*, Yoshiaki Sato^*, Masanori Nagata^*, Takaaki Goto^* and Junichi Goto^1,*,

^* Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba, Sendai 980-8578, Japan
Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba, Sendai 980-8574, Japan

¹ To whom correspondence should be addressed. e-mail: jun-goto{at}mail.pharm.tohoku.ac.jp

We have previously demonstrated that the rat brain contains three unconjugated bile acids, and chenodeoxycholic acid (CDCA) is the most abundantly present in a tight protein binding form. The ratio of CDCA 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 CDCA in rat brain. In this study, we have demonstrated the existence of an enzymatic activity that converts 3ß-hydroxy-5-cholenoic acid into CDCA in rat brain tissue. To distinguish marked compounds from endogenous related compounds, ¹⁸O-labeled 3ß-hydroxy-5-cholenoic acid, 3ß,7-dihydroxy-5-cholenoic acid, and 7-hydroxy-3-oxo-4-cholenoic acid were synthesized as substrates for in vitro incubation studies. The results clearly suggest that 3ß-hydroxy-5-cholenoic acid was converted to 3ß,7-dihydroxy-5-cholenoic acid by microsomal enzymes. The 7-hydroxy-3-oxo-4-cholenoic acid was produced from 3ß,7-dihydroxy-5-cholenoic acid by the action of microsomal enzymes, and ⁴-3-oxo acid was converted to CDCA by cytosolic enzymes.

These findings indicate the presence of an enzymatic activity that converts 3ß-hydroxy-5-cholenoic acid into CDCA in rat brain tissue. Furthermore, this synthetic pathway for CDCA may relate to the function of 24S-hydroxycholesterol, which plays an important role in cholesterol homeostasis in the body.

Abbreviations: CDCA, chenodeoxycholic acid; ESI, electrospray ionization; FXR, farnesoid X receptor; HSD, hydroxysteroid dehydrogenase; IS, internal standard; LC/MS, liquid chromatography/mass spectrometry; Rk, relative retention factor

Supplementary key words biosynthesis • brain bile acid • cholesterol homeostasis • stable isotope dilution

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