Glycocholic acid and glycodeoxycholic acid but not glycoursocholic acid inhibit bile acid synthesis in the rabbit.

Feedback regulation of derepressed hepatic bile acid biosynthesis was studied individually with glycocholic, glycodeoxycholic, and glycoursocholic acids by infusion into bile acid-depleted rabbits. Construction of a bile fistula drained the endogenous bile acid pool (90% glycodeoxycholic acid, 10% glycocholic acid) within 24 hours and elicited maximal bile acid synthesis after about 72 hours, at which time glycocholic acid became the only biliary bile acid (greater than 98%). Replacement of the bile acid pool with glycocholic acid or glycodeoxycholic acid at a rate equivalent to the hepatic endogenous bile acid flux inhibited endogenous biosynthesis by 40%. In contrast, glycoursocholic acid, the 7 beta-hydroxy epimer of glycocholic acid, failed to suppress synthesis. Hepatic bile acid depletion increased hydroxymethyglutary coenzyme A (HMG-CoA) reductase activity fourfold and cholesterol 7 alpha-hydroxylase activity threefold, which were reduced 48% and 51%, respectively, from their maximum levels during replacement with glycocholic acid. Glycodeoxycholic acid infusion depressed cholesterol 7 alpha-hydroxylase activity by 59% without reducing HMG-CoA reductase activity significantly. There was no significant change in the activity of either enzyme during glycoursocholic acid infusion. Biliary cholesterol and cholestanol secretion declined 13% and 53%, respectively, during glycocholic acid infusion, were not affected by glycodeoxycholic acid infusion, but increased 19% and 43%, respectively, during glycoursocholic acid infusion. These results show that in rabbits the feedback regulation of hepatic bile acid synthesis depends on the hepatic flux of the normally present endogenous bile acids glycocholic acid and glycodeoxycholic acid but does not respond to the 7 beta-hydroxy glycoursocholic acid. Glycocholic acid inhibits both HMG-CoA reductase and cholesterol 7 alpha-hydroxylase while glycodeoxycholic acid affects primarily cholesterol 7 alpha-hydroxylase. Thus, the regulation of bile acid synthesis may be mediated by both the availability of cholesterol substrate and the activity of the rate-determining enzyme for bile acid synthesis.

Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: a 30-month pilot study.

We investigated the effects of once-daily oral administration of 10 mg/kg ursodeoxycholic acid (generic name, ursodiol) on elevated serum enzyme activities, bilirubin, cholesterol, bile acids and symptoms in patients with primary sclerosing cholangitis. A 30-mo, open-label, pilot trial was designed to cover four periods: (a) 3 mo of pretreatment observation (period 1), (b) 6 mo on ursodiol (period 2), (c) 3 mo withdrawal of treatment (period 3) and (d) 18 mo of extended retreatment (period 4). Diagnosis was confirmed by cholangiography and liver biopsy specimens. We enrolled 12 patients with persistently elevated pretreatment alkaline phosphatase and gamma-glutamyltransferase levels (at least twice the upper limit of normal), and observed them for a median of 37 mo. Significant reductions in serum total cholesterol levels and in serum enzyme activities indicating cholestasis and hepatocellular injury occurred during ursodiol treatment in both treatment periods 2 and 4 and relapsed with treatment interruption in period 3. Elevated serum bilirubin and symptoms of disabling fatigue, pruritus and diarrhea were improved by ursodiol. Improvements have continued after 2 yr of treatment in 10 patients (1 patient had a transplantation after he relapsed on withdrawal of ursodiol therapy; another died of postoperative complications of colon resection for carcinoma). No other cases of clinical deterioration were observed in the retreatment period. The longer term reductions of alkaline phosphatase, transaminases, bilirubin and cholesterol after 2 yr of treatment were even greater than the initial reductions after 6 mo of treatment. These results justify initiation of larger, controlled clinical trials, with serial morphological evaluations of the liver and biliary tree.