The Biosynthesis of Bile Acids and Its Regulation

The bile acids cholic acid and chenodeoxycholic acid are synthesized from cholesterol in the liver (Dl, S3). Several structural modifications are necessary to convert cholesterol, with its 27 carbon atoms, C-5,6 double bond and 3p-hydroxyl group, to a 24-carbon atom, saturated, 3,7 and 12a-hydroxyl-ated bile acid. The major reactions in this transformation are shown in Figs. 3 and 4. The reactions are catalyzed by mitochondrial, microsomal, soluble, and possibly peroxisomal enzymes. 

During bile acid biosynthesis, modifications to the cyclopentanophen-anthrene (steroid) nucleus are thought to precede the oxidation and cleavage of the cholesterol side chain. The first and rate-controlling step in bile acid synthesis is the 7o-hydroxylation of cholesterol (I) to form 7a-hydroxy-choles-terol (II) (Fig. 3). This step is catalyzed by cholesterol 7a-monooxygenase (cholesterol 7a-hydroxylase) (EC 1.14.13.17), a microsomal enzyme (M37). Further metabolism of 7a-hydroxy-cholesterol involves oxidation of the 3p-hydroxyl group and isomerization of the double bond from C-5,6 to C-4,5, 

Two pathways have been proposed for degradation of the cholestane side chain in the biosynthesis of bile acids. These differ in the site proposed for the first hydroxylation step in side-chain oxidation and are discussed below for the formation of cholic add. 

26-Hydroxylation pathway. The mitochondrial fraction of both human and rat liver contains a 26-hydroxylase enzyme (B23), which can convert 5fi-cholestane-3a, 7a, 12a-triol (V) to 5ff-cholestane-3a,7o,12o,26-tetrol (VII) (Fig. 4). This tetrol is oxidized to 3a,7a,12a-trihydroxy-5p-cholestan-26-oic acid (THCA, VIII) by liver cytosol (C5). Further hydroxylation at C-24 forms varanic acid (IX) and its side chain is then shortened with oxidation at C-24 to yield cholic acid (X) (Fig. 4). 

25-HydroxylaHon pathway. This alternative pathway has been demonstrated in both rat and human liver (S24). It involves die 25-hydroxylation of 5P-cholestane-3a,7a,12a-trioI (V) togive5p-cholestane-3a,7a,12a,25-tetrol (XI), followed by 24S-hydroxylation to yield 5fi-cholestane-3a,7a,12a, 

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