Effects of Long Term Feeding of Chenodeoxycholic Acid on Biosynthesis and Metabolism of Bile Acids in the Rat

Chenodeoxycholic acid was fed to rats at the 1% level in the diet for up to 2 months, and the effects on several hydroxylations in the biosynthesis and metabolism of bile acids as well as on the composition of biliary bile acids were studied. The hydroxylations assayed were 7α-hydroxylation of cholesterol, 12α-hydroxylation of 7α-hydroxy-4-cholesten-3-one and 5β-cholestane-3α, 7α-diol, 26-hydroxylation of 5β-cholestane-3α, 7α-diol, 6β-hydroxylation of taurochenodeoxycholic acid and lithocholic acid, and 7α-hydroxylation of taurodeoxycholic acid. All these hydroxylations are catalyzed by the microsomal fraction of liver homogenate in the presence of NADPH. The 7α-hydroxylation of cholesterol and the 12α-hydroxylation of 7α-hydroxy-4-cholesten-3-one and 5β-cholestane-3α, 7α-diol were inhibited by 50% or more after feeding chenodeoxycholic acid for 2 weeks or longer. The 26-hydroxylation of 5β-cholestane-3α, 7α-diol was not inhibited. The 6β-hydroxylation of taurochenodeoxycholic acid and lithocholic acid was stimulated by about 50% after 4 weeks of feeding chenodeoxycholic acid. The extent of stimulation was somewhat greater after 8 weeks. The 7α-hydroxylation of taurodeoxycholic acid was stimulated by 20 to 80% by chenodeoxycholic acid. The effects of chenodeoxycholic acid on the various hydroxylations were readily reversible. Thus, the rates of the various hydroxylations in rats fed chenodeoxycholic acid for 3 or 8 weeks, and, subsequently, control diet for 1 week did not differ significantly from those in the corresponding controls. Similarly, in rats fed chenodeoxycholic acid for 3 weeks and subjected subsequently to biliary drainage and starvation for 2 days, the extent of stimulation of 7α-hydroxylation of cholesterol and 12α-hydroxylation of 7α-hydroxy-4-cholesten-3-one was the same as in the controls. The composition of biliary bile acids was determined after 3 weeks of feeding chenodeoxycholic acid. Cholic acid and deoxycholic acid were virtually absent. However, after 1 day of biliary drainage, the rats previously fed chenodeoxycholic acid started to synthesize cholic acid.