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

Abstract

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 3β-hydroxy-5-cholenoic acid into CDCA in rat brain tissue. To distinguish marked compounds from endogenous related compounds, 18O-labeled 3β-hydroxy-5-cholenoic acid, 3β,7α-dihydroxy-5-cholenoic acid, and 7α-hydroxy-3-oxo- 4-cholenoic acid were synthesized as substrates for in vitro incubation studies. The results clearly suggest that 3β-hydroxy-5-cholenoic acid was converted to 3β,7α-dihydroxy-5-cholenoic acid by microsomal enzymes. The 7α-hydroxy-3-oxo-4-cholenoic acid was produced from 3β,7α- dihydroxy-5-cholenoic acid by the action of microsomal enzymes, and δ4-3-oxo acid was converted to CDCA by cytosolic enzymes. These findings indicate the presence of an enzymatic activity that converts 3β-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.