Pathways for Primary Bile Salt Formation in Man

The pathways for primary bile salt synthesis shown in Fig. 2 are derived from studies in man (3-7) and are believed to represent the major synthetic routes. Several of the intermediates shown in Fig. 2 have been isolated from human bile. Trihydroxycoprostanic acid, XV, has been crystallized from human fistula bile (8) and shown to be derived from cholesterol (4,5). The major metabolite of trihydroxycoprostanic acid in man is cholic acid (5). 5/5-Cholestane-3a,7a-diol, X, has been identified as a product of cholesterol oxidation (6) and 3a,7a-dihydroxycoprostanic acid, XI, has been isolated from human fistula bile (7). 

In addition to these naturally occurring compounds in human bile, a number of other intermediates have been identified in fractions of human liver homogenates (3) and are shown in Fig. 2 as compounds VI, VII, VIII, IX, X, XIII, XIV. 

The observations upon which the pathways in Fig. 2 are based are consistent with the view (14) that oxidation of the cholesterol side chain inhibits 12a-hydroxylation. The 12a-hydroxylase enzyme (or enzymes) ap- 

Chenodeoxycholate synthesis may possibly proceed along several pathways. As shown in Fig. 2, one route is similar to that for cholate, in which ring alterations are completed before side-chain oxidation. A second suggested route begins with the oxidation of a terminal methyl group of cholesterol, yielding 26-hydroxycholesterol (9,10), which is readily converted to chenodeoxycholate but not cholate in the rat. Such a route involving 26-hydroxy-cholesterol remains speculative in man, however, as this compound has not yet been identified as a metabolite of cholesterol in human bile and there is some recent evidence that 26-hydroxycholesterol is not an important intermediate in bile salt formation (11). 

The reaction sequence in the conversion of cholesterol into 5/5-choles-tane-3a,7a,12a-triol and 5/5-cholestane-3a,7a-diol has been shown to be the same in human and rat liver homogenates (3). All of these reactions occur with the 20,000g supernatant fluid of homogenates of human liver. The 12a-hydroxylation of 7a-hydroxycholest-4-en-3-one proceeds efficiently in the presence of a microsomal fraction fortified with NADPH (3). 

---