Potential bile acid precursors in plasma—Possible indicators of biosynthetic pathways to cholic and chenodeoxycholic acids in man

Abstract

The plasma concentrations of 3β-hydroxy-5-cholestenoic acid, 3β,7α-dihydroxy-5-cholestenoic acid and 7α-hydroxy-3-oxo-4-cholestenoic acid have been compared with that of 7α-hydroxy-4-cholesten-3-one in healthy subjects and in patients with an expected decrease or increase of the bile acid production. In controls and patients with liver disease, the level of 7α-hydroxy-3-oxo-4-cholestenoic acid was positively correlated to that of 3β,7α-dihydroxy-5-cholestenoic acid and not to that of 7α-hydroxy-4-cholesten-3-one. In patients with stimulated bile acid formation the levels of the acids were not correlated to each other but there was a significant positive correlation between the levels of 7α-hydroxy-3-oxo-4-cholestenoic acid and 7α-hydroxy-4-cholesten-3-one. These findings indicate that the precursor of 7α-hydroxy-3-oxo-4-cholestenoic acid differs depending on the activity of cholesterol 7α-hydroxylase. Since the activity of this enzyme is reflected by the level of 7α-hydroxy-4-cholesten-3-one in plasma the findings are compatible with a formation of 7α-hydroxy-3-oxo-4-cholestenoic acid from 3β,7α-dihydroxy-5-cholestenoic acid when the rate of bile acid formation is normal or reduced and from 7α-hydroxy-4-cholesten-3-one under conditions of increased bile acid synthesis. In support of this interpretation, 7α,26-dihydroxy-4-cholesten-3-one was identified at elevated levels in plasma from patients with ileal resection or treated with cholestyramine. The levels of 7α,12α-dihydroxy-4-cholesten-3-one were also higher than normal in these patients.

Based on these findings and previous knowledge, a model is proposed for the biosynthesis of bile acids in man. Under normal conditions, two major pathways, one “neutral” and one “acidic” or “26-oxygenated”, lead to the formation of cholic acid and chenodeoxycholic acid, respectively. These pathways are separately regulated. When the activity of cholesterol 7α-hydroxylase is high, the “neutral” pathway is most important whereas the reverse is true when cholesterol 7α-hydroxylase activity is low. In cases with enhanced activity of cholesterol 7α-hydroxylase, the “neutral” pathway is connected to the “acidic” pathway via 7α,26-dihydroxy-4-cholesten-3-one, whereas a flow from the acidic pathway to cholic acid appears to be of minor importance.