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EC number: 249-070-6 | CAS number: 28535-81-1
The discussion is based on articles of "Clinical pharmacokinetics of therapeutic bile acids" and "Italian Journal of Gastroenterology" and on data from the DrugBank database.
Bile acids are endogenous substances in humans. They are produced from cholesterol, of which they represent the major metabolic fate. They are secreted from the liver, stored in the gallbladder, and passed through the bile duct into the intestine, where they emulsify dietary lipids and thereby promote fat digestion and absorption, thanks to their detergent properties. Most of the bile acids are secreted into the upper small intestine, absorbed in the lower small intestine and returned to liver for reuse, in a process called enterohepatic circulation(1).
The most abundant bile acids in humans are cholic acid and chenodeoxycholic acid. In other mammals deoxycholic acid is another common bile acid. In liver, bile acids are conjugated with amino acids, mainly glycine and taurine, to give bile salts (glycholte and taurocholate). Their biosynthesis in liver involves a series of hydroxylations catalyzed by microsomal P450 mixed-function oxidases(1). The first hydroxylation occurs at C-7 and plays a major role in controlling the overall pathway. This reaction is inhibited by cholic acid through a negative feed-back mechanism(2). The other hydroxylations occurs at C-3 and C-12. The dehydrogenation of the hydroxyl in C-3 to a ketone, followed by its reduction back to a hydroxyl group, inverts the configuration of the molecule(1).
Once in the intestine, the natural bacterial flora can dehydroxylate secreted bile acids (or primary bile acids) in C-7 and produce the secondary bile acids (lithocholic acid and deoxycholic acid)(2).
According to Crosignani et al. (1996), if administered by oral route, the similar substance ursodeoxycholic acid is not well absorbed by the gastrointestinal tract. The absorption of the similar substance ursodeoxycholic acid in the small intestine is slow and incomplete because of the low solubility of the substance. Chenodeoxycholic acid, instead, is well absorbed by the intestine and 7-ketolithocholic acid has an excellent colonic absorption (Walker et al., 1985). According to Walker et al. (1985) 7-ketolithocholic acid has an excellent colonic absorption and, in this study, the absorption of 7-ketolithocholic acid in jejunum, ileum, and colon was equal to the absorption of ursodeoxycholic and chenodeoxycholic acid. Absorption rates of 7-ketolithocholic, ursodeoxycholic, and chenodeoxycholic acid indicate, that substitution of the 7- hydroxyl group by the 7-keto group has no influence on the intestinal absorption of bile acids. Moreover, the absorption of bile acids by diffusion occurs in all the intestine, while the active transport only occurs in the terminal ileum.
Also ursodeoxycholic acid and chenodeoxycholic acid administered by diet are efficiently extracted by liver, like endogenous bile acids. Once in the liver, they are conjugated with glycerine and taurine and then secreted in the bile. Afterwards they undergo into the enterohepatic circulation (resulting in low serum concentrations) together with the other bile salts and, despite the rapid hepatic extraction, the clearance of these substances is low because of the enterohepatic recirculation.
In liver, 7-ketolithocholic acid is extensively reduced to chenic acid and, to lesser extent, to ursodeoxycholic acid. Hepatic reduction is similar for both unconjugated as well as glycine- and taurine-conjugated 7-ketolithocholic acid. These studies indicate that 7-ketolithocholic acid is likely to be a physiological precursor of ursodeoxycholic acid in healthy man (Fromm H et al., 1980).
The conjugated 7-ketolithocholic acid, especially the taurine conjugated, is predominantly reduced to chenodeoxycholic acid, whereas the unconjugated 7-ketolithocholic acid is not reduced well to either chenodeoxycholic acid or ursodeoxycholic acid. Thus, the reduction of 7-ketolithocholic acid by human liver enzymes has been found to be dependent on whether the substrate was conjugated or not (Amuro Y et al., 1989).
As the endogenous bile acids, also exogenous bile acids undergo to bacterial metabolism in the intestine.
7-Ketolithocholic acid is the major intermediate in the intestinal bacterial conversion of chenodeoxycholic to ursodeoxycholic acid (Fedorowski et al., 1979). The reduction of 7-ketolithocholic to ursodeoxycholic acid proceeded significantly faster anaerobically and at acid pH than under aerobic and alkaline conditions (Fromm et al., 1983). According to the study of Fedorowski et al. (1979), 80% of the administered chenodeoxycholic acid and 41% of the administered ursodeoxycholic acid were 7-dehydroxylated to lithocholic acid during 2 hours of incubation. These data may suggest that chenodeoxycholic acid and ursodeoxycholic acid are interconvertible via 7-ketolithocholic acid by the mixed culture of human intestinal microorganisms under an anaerobic condition. In the same study, the intestinal flora of several subjects converted chenodeoxycholic acid to ursodeoxycholic acid without the accumulation of the hypothetical intermediate7-ketolithocholic acid. These results indicate that the fecal bacterial flora is capable of 7-dehydroxylating chenodeoxycholic acid and ursodeoxycholic acid to yield lithocholic acid. Apparently the enzymes involved are relatively stereospecific since the 7 beta-hydroxy group of ursodeoxycholic acid was removed more slowly than the 7 alpha-hydroxy group of chenodeoxycholic acid.
Daily elimination of endogenous bile acids (about 0.5 g/day or less) proceed through the feces(1). The elimination of ursodeoxycholic acid and chenodeoxycholic acid administered by diet, unmodified or after bacterial biotransformation to lithocholic acid, occurs mainly by feces (Crosignani A et al., 1996).
(1)Mathews CK et al., 2000. Biochemistry. Third edition. Addison Wesley Longman International Editions.
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