An in vivo evaluation of the quantitative significance of several potential pathways to cholic and chenodeoxycholic acids from cholesterol in man

The present study was designed to obtain more definitive information in man on the metabolic pathways to chenodeoxycholic acid and to cholic acid via a pathway not involving an initial 7a-hydroxylation of cholesterol. Four bile fistula patients were administered consecutively two or more of the following 3H-labeled bile acid inter- mediates: 7a-hydroxycholestero1, 7a-hydroxy-4-cholesten- %one, 5P-cholestane 3a,7a,26-triol, 26-hydroxycholestero1, 7a1,26-dihydroxy-4-cholesten-3-one, and 5-cholestene-SP,- 12a-diol. Both 7a-hydro~y(7/3-~H)cholesterol and 7a- hydro~y-4-(6/3-~H)cholesten-3-0ne were efficiently con- verted to bile acids and preferred chenodeoxycholic acid over cholic acid. The specific activity time curves indicated that a portion of cholic acid synthesis did not pass through 7a-hydroxycholesterol. (3H)26-Hydroxycholesterol and (3H)- 5-cholestene 3P, 12a-diol, two potential intermediates of this bypass pathway to cholic acid, were poorly converted to primary bile acids (10 to 27%). The (3H)26-hydroxy- cholesterol preferred chenodeoxycholic over cholic acid by about 4 to 1. The (3H)5-cholestene 3/3,12a-diol formed cholic acid in low yield (10 to 20%). It is concluded that pathways to primary acids from cholesterol through 26-hydroxycholestero1 and 5-cholestene 3/3,12a-diol are probably of minor quantitative significance. A selective pathway to chenodeoxycholic acid via 26-hydroxylation of 7a-hydroxy-4-cholesten-3-one was also investigated. The 5P-cholestane 3a,7a,26-triol was converted in about equal amounts to cholic and chenodeoxycholic acids. The 7a- hydroxy-4-cholesten-3-one was also efficiently converted to both bile acids but preferred chenodeoxycholic acid. The most efficient precursor of chenodeoxycholic acid was 7a,26-dihydroxy-4-cholesten-3-one, which was efficiently converted to primary bile acids; chenodeoxycholic acid was preferred over cholic acid by approximately 7 to 1. These findings suggest the presence of a major pathway to cheno- deoxycholic acid via the 26-hydroxylation of 7a-hydroxy-4- cholesten-3-one and intermediate formation of 7a,26- dihydroxy-4-cholesten-3-one.-Swell L., J. Gustafsson, C. C. Schwa-, L. G. Halloran, H. Danielsson, and 2. R. Vlahcevic. An in vivo evaluation of the quantitative sig- nificance of several potential pathways to cholic and cheno- deoxycholic acids from cholesterol in man.