Bile acid metabolism in cirrhosis. VIII. Quantitative evaluation of bile acid synthesis from [7 beta-3H]7 alpha-hydroxycholesterol and [G-3H]26-hydroxycholesterol.
In order to evaluate more definitively the observed aberrations in the synthesis of cholic and chenodeoxycholic acids in patients with advanced cirrhosis, two bile acid biosynthesis pathways were examined by determining the efficiency of conversion of [3H]7 alpha-hydroxycholesterol and [3H] 26-hydroxycholesterol to primary bile acids. Bile acid kinetics were determined by administration of [14C]cholic and [14C]chenodeoxycholic acids. Cholic acid synthesis in cirrhotic patients was markedly depressed (170 vs. 927 mumoles per day)( while chenodeoxycholic acid synthesis was reduced to a much lesser degree (227 vs. 550 mumoles per day). The administration of [3H]7 alpha-hydroxycholesterol allowed for an evaluation of the major pathway of bile acid synthesis via the 7 alpha-hydroxylation of cholesterol. This compound was efficiently incorporated into primary bile acids by the two normal subjects (88 and 100%) and two cirrhotic patients (77 and 91%). However, the recovery of the label in cholic acid was slightly less in cirrhotic patients than in normal subjects. [3H]26-hydroxycholesterol was administered to ascertain the contribution of the 26-hydroxylation pathway to bile acid synthesis. All study subjects showed poor conversion (9 to 22%) of this intermediate into bile acids. The results of this study suggest that a major block in the bile acid synthesis pathway in cirrhosis is at the level of 7 alpha-hydroxylation of cholesterol (impairment of 7 alpha-hydroxylase) and /or in the feedback triggering mechanism regulating bile acid synthesis. The data also suggest that the 26-hydroxylation pathway in normal subjects and patients with cirrhosis is a minor contributor to synthesis of the primary bile acids. Therefore, the relative sparing of chenodeoxycholic acid synthesis observed in cirrhotic patients is not due to preferential synthesis of this bile acid via the 26-hydroxylation pathway.
D000328:Adult; D001647:Bile Acids and Salts / Q000032:analysis / Q000096:biosynthesis*; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D002793:Cholic Acids / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D007700:Kinetics; D008103:Liver Cirrhosis / Q000378:metabolism*; D008875:Middle Aged; D014316:Tritium
D001647:Bile Acids and Salts; D002793:Cholic Acids; D006888:Hydroxycholesterols; D002635:Chenodeoxycholic Acid; D014316:Tritium; C007042:cholest-5-ene-3 beta,26-diol; C011724:cholest-5-en-3 beta,7 alpha-diol