Bile Acid Synthesis

Cholesterol is the obligatory precursor of bile acids, and the liver is the sole source and site of bile acid formation (1). In the transformation of choles­ terol to bile acids, the cyclopentanophenanthrene nucleus is first believed to undergo modifications followed by oxidation and cleavage of the choles­ terol side-chain. The key reactions transforming the nucleus are illustrated in Figure 1. The first and perhaps most important step in bile acid synthesis is the 7 a-hydroxylation of cholesterol to form 7a-hydroxycholesterol (II). This reaction is catalyzed by the microsomal enzyme system, cholesterol 70'­ hydroxylase (EC 1.14), which determines the rate of bile acid formation, but the detailed mechanism of enzyme control is not known. The 7a-hydroxy­ cholesterol that is formed is totally committed to bile acid production (2, 3) with the next steps involving oxidation of the hydroxyl group at C-3 and isomerization of the double bond from C-5,6 to C-4,5, which yields 70'­ hydroxy-4-cholesten-3-one (III). This compound is the last intermediate common to both cholic acid and chenodeoxycholic acid. In cholic acid synthesis, 12a-hydroxylation occurs to yield 7a,12a-dihydroxy-4-choles­ ten-3-one (IV), which then undergoes reduction of the double-bond at C 4-5 and the ketone at C-3 to give 5,8-cholestane-3a,7a,12a-triol (V). Thus far,