In man bile acid synthesis has a distinct circadian rhythm but the relationship of this rhythm to feedback inhibition by bile acid is unknown. We measured bile acid synthesis as release of 14C02 from [26-14C]cholesterol every 2 hr in three normal volunteers during five separate 24-hr periods. Data were fitted by computer to a cosine curve to estimate amplitude and acrophase of the circadian rhythm. In an additional six volunteers, we measured synthesis every 2 h r from 8:OO a.m. to 4:OO p.m. only. During the control period, amplitude (expressed as percentage of mean synthesis) averaged 52% and acrophase averaged 6:49 a.m. During administration of ursodeoxycholic acid (15 mg per kg per day), synthesis averaged 126% of baseline (p < O.l), amplitude averaged 43% and acrophase averaged 6:20 a.m. During administration of chenodeoxycholic acid (15 mg per kg per day), synthesis averaged 43% of baseline (p < 0.001), amplitude averaged 53% and acrophase averaged 9:04 a.m. Addition of prednisone to this regimen of chenodeoxycholic acid to eliminate release of 14C02 from corticosteroid hormone synthesis resulted in a mean amplitude of 62% and a mean acrophase of 6 5 0 a.m., values very similar to those in the baseline period. Administration of prednisone alone also did not significantly alter the baseline amplitude (40%) or acrophase (6:28 a.m.). We conclude that neither chenodeoxycholic acid nor ursodeoxycholic acid significantly alters the circadian rhythm of bile acid synthesis in man. Moreover, because this method of measuring synthesis does not require subtraction of large amounts of exogenous bile acid, these data also demonstrate more clearly than ever before that chenodeoxycholic acid causes inhibition of total bile acid synthesis while ursodeoxycholic acid causes either no change or a slight increase in synthesis.
Hepatic production of bile acids is a major catabolic route for cholesterol elimination (1) and also provides detergent for solubilization of biliary cholesterol (2). However, regulation of bile acid synthesis remains incompletely defined, especially in man. Negative feedback