Bile Acid Metabolism in Cirrhosis. VIII. Quantitative Evaluation of Bile Acid Synthesis From [7β-3H]7α-Hydroxycholesterol and [G-3H]26-Hydroxycholesterol

Authors

  • Marc Goldman,

    1. Division of Gastroenterology, Veterans Administration Medical Center, Medical College of Virginia, Richmond, Virginia 23249 and Departments of Pediatrics and Pharmaceutical Biochemistry, University of Uppsala, Uppsala, Sweden
    Search for more papers by this author
  • Z. Reno Vlahcevic,

    Corresponding author
    1. Division of Gastroenterology, Veterans Administration Medical Center, Medical College of Virginia, Richmond, Virginia 23249 and Departments of Pediatrics and Pharmaceutical Biochemistry, University of Uppsala, Uppsala, Sweden
    • Z. R. Vlahcevic, M.D., Division of Gastroenterology (151), Veterans Administration Medical Center, 1201 Broad Rock Road, Richmond, Virginia 23249.
    Search for more papers by this author
  • Charles C. Schwartz,

    1. Division of Gastroenterology, Veterans Administration Medical Center, Medical College of Virginia, Richmond, Virginia 23249 and Departments of Pediatrics and Pharmaceutical Biochemistry, University of Uppsala, Uppsala, Sweden
    Search for more papers by this author
  • Jan Gustafsson,

    1. Division of Gastroenterology, Veterans Administration Medical Center, Medical College of Virginia, Richmond, Virginia 23249 and Departments of Pediatrics and Pharmaceutical Biochemistry, University of Uppsala, Uppsala, Sweden
    Search for more papers by this author
  • Leon Swell

    1. Division of Gastroenterology, Veterans Administration Medical Center, Medical College of Virginia, Richmond, Virginia 23249 and Departments of Pediatrics and Pharmaceutical Biochemistry, University of Uppsala, Uppsala, Sweden
    Search for more papers by this author

Abstract

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]7α-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 μmoles per day) while chenodeoxycholic acid synthesis was reduced to a much lesser degree (227 vs. 550 μmoles per day). The administration of [3H]7α-hydroxycholes-terol allowed for an evaluation of the major pathway of bile acid synthesis via the 7α-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 7α-hydroxylation of cholesterol (impairment of 7α-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.

Ancillary