Bile acids, primary

The primary bile acids are synthesized in the liver from cholesterol. These are cholic acid (found in the largest amount) and chenodeoxycholic acid (Figure 26-7). 

A portion of the primary bile acids in the intestine is subjected to further changes by the activity of the intestinal bacteria. These include deconjugation and 7a-dehydroxylation, which produce the secondary bile acids, deoxycholic acid and hthocholic acid. 

Oelkers, P., et al. Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2). J. Clin. Invest. 1997, 99, 1880-1887. 

Figure 1.1 The classic pathway for the conversion of cholesterol into the primary bile acids CA and CDCA, involving the 7 a-hydroxylase enzyme (also known as CYP7A1). Simplified from Dr John Chiang/ The 7 OH group is highlighted with the shaded circle. This group is cleaved to produce the secondary BAs DCA and LCA.

The 7a-dehydroxylation is the most important bacterial transformation of bile acids, rapidly forming secondary from primary bile acids and is seemingly... 

Assays have also made use of 7a-hydroxysteroid dehydrogenase that can measure the primary bile acids, or for more specialised purposes such as differentiating between pathways of bile-acid synthesis to determine the proportion derived from the acid pathway. 

Figure 5.2 Therapeutic interventions for decreasing colorectal mucosal bile acid exposure as a CRC chemoprevention strategy. 1) Lifestyle modifications including reduction in dietary animal fat and increased fibre intake may, at least partly, be explained by reduction in luminal primary (cholic acid [CA] and chenodeoxycholic acid [CDCA]) and secondary (deoxycholic acid [DCA] and lithocholic acid [LCA]) bile acids. 2) Reduction of secondary bile acids, which are believed to have pro-carcinogenic activity could be obtained by decreased bacterial conversion from primary bile acids. 3) Alternatively, bile acids could be sequestered by chemical binding agents, e.g. aluminium hydroxide (Al(OH)3) or probiotic bacteria. 4) Exogenous ursodeoxycholic acid (UDCA) can reduce the luminal proportion of secondary bile acids and also has direct anti-neoplastic activity on colonocytes in vitro.

Alternative potential strategies for reduction of mucosal secondary bile acid exposure are to target deconjugation of glycine/taurine bile salts by bacterial bile salt hydrolases and/or bacterial 7-dehydroxylation of primary bile acids to secondary bile acids. Sequestration of bile acids in the intestinal lumen using probiotic bacteria has also been proposed as an area for future research. ... 

A and B are in cis position relative to each other (see p. 54). One to three hydroxyl groups (in a position) are found in the steroid core at positions 3, 7, and 12. Bile acids keep bile cholesterol in a soluble state as micelles and promote the digestion of lipids in the intestine (see p.270). Cholic add and cheno-deoxychoMc acid are primary bile acids that are formed by the liver. Their dehydroxylation at C-7 by microorganisms from the intestinal flora gives rise to the secondary bile acids lithocholic acid and deoxycholic acid. 

Cholic acid and chenodeoxycholic acid, known as the primary bile acids, are quantitatively the most important metabolites of cholesterol. After being biosynthesized, they are mostly activated with coenzyme A and then conjugated with glycine or the non-pro-teinogenic amino acid taurine (see p. 62). The acid amides formed in this way are known as conjugated bile acids or bile salts. They are even more amphipathic than the primary products. 

Intestinal bacteria produce enzymes that can chemically alter the bile salts (4). The acid amide bond in the bile salts is cleaved, and dehydroxylation at C-7 yields the corresponding secondary bile acids from the primary bile acids (5). Most of the intestinal bile acids are resorbed again in the ileum (6) and returned to the liver via the portal vein (en-terohepatic circulation). In the liver, the secondary bile acids give rise to primary bile acids again, from which bile salts are again produced. Of the 15-30g bile salts that are released with the bile per day, only around 0.5g therefore appears in the feces. This approximately corresponds to the amount of daily de novo synthesis of cholesterol. 

Bacteria in the intestine can remove glycine and taurine from bile salts, regenerating bile acids. They can also convert some of the primary bile acids into "secondary" bile acids by removing a hydroxyl group, producing deoxycholic acid from cholic acid and lithocholic acid from chenodeoxycholic acid (Figure 18.11). 

Names, structural char acteristics, and func tions of bile acids The primary bile acids, cholic or chenodeoxycholic acids, contain two or three alcohol groups, respectively. Both have a shortened side chain that terminates in a carboxyl group. These structures are amphipathic, and can serve as emulsifying agents. 

Some dietary factors can also change the bile acid species and, by doing so, alter cholesterol absorption. The liver synthesizes the primary bile acids, cholic and chenodeoxycholic acid. Bacteria in the intestine can convert some of the primary bile acids into secondary bile acids, producing deoxycholic from cholic acid and lithocholic from chenodeoxycholic acid. When certain dietary components alter the intestinal microflora, the rate of secondary bile... 

It is well known that bile acids are produced in the liver of vertebrates for digestion and absorption of fats and fat-soluble vitamins. Starting from isoprene, a series of biochemical reactions yield a key compound, cholesterol, which is converted to primary bile acids, such as cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) and lithocholic acid (LCA). Hereafter the abbreviations of bile acid derivatives can be seen by consulting Table 1 and Figure 1. 

As already pointed out, cysteine may be metabolized to pyruvate, or it can be oxidized to cystine. It can also be converted to taurine, NH3+-CH2-CH2-S03. Taurine is obtained by oxidizing the -SH group of cysteine and losing the carboxyl group of decarboxylation. Taurine is quite abundant in most tissues and is said to be the most abundant "amino acid" of the human organism. One of its functions is to conjugate primary bile acids (Chapter 19). 

Bile acids are steroids, characterised by a carbon skeleton with four fused rings, generally arranged in a 6-6-6-S fashion. Primary bile acids are cholic acid and chenodeoxycholic acid (Figure 6.2). Within the intestines, bacteria convert primary bile acids to secondary bile acids, for example deoxycholate (from cholate) and lithocholate (from chenodeoxycholate). Both primary and secondary bile acids are re-absorbed by the intestines and delivered back to the liver via the portal circulation. 

Figure 6.2 Synthesis of primary bile acids from cholesterol. 

Biosynthesis of the two primary bile acids is followed by conjugation of their carboxylic group with the amino group of either glycine or taurine, mediated by a cytoplasmic enzyme. By means of this conjugation, the primary bile acids, which initially are barely water-soluble, become anions and are thus rendered hydrophilic. In this way four conjugated bile acids are formed ... 

Hvdroxvlation pathway An alternative explanation for the bile acid synthetic defect in CTX has been proposed by Oftebro and colleagues which starts via 26-hydroxylation of 5P-cholestane-3a,7a,12a-triol (IX, Fig. lOa and 10b). In this pathway the mitochondrial fraction of both human and rat liver contains a 26-hydroxylase enzyme (63) which can convert 5P-cholestane-3a,7a,12a-triol (IX ) to 5P-cholestane-3a,7a,12a,26-tetrol (XI) (Fig. 10a and 10b ). This tetrol is oxidized to 3a,7a,12a-trihydroxy-5P-cholestan-26-oic acid (THCA, XII) by liver cytosol (2,64). Further hydroxylation at C-24 forms varanic acid (XIV) and its side chain is shortened with oxidation at C-24 to yield cholic acid (X,Fig. 10 a). These investigators demonstrated diminished mitochondrial 26-hydroxylation of 5p-cholestane-3a,7a,12a-triol and 5P-cholestane-3a,7a-diol, possible precursors for cholic acid and chenodeoxycholec acid in CTX liver. As a consequence, neither 26-hydroxylated intermediates can be formed so that total primary bile acid synthesis would be diminished. Accordingly, the accumulation of 5P-cholestane-3a,7a,12a,25-tetrol arises from 25-hydroxylation of 5P-cholestane-3a,7a,12a-triol by the alternative microsomal 25-hydroxylation mechanism. 

Patteson, T. E., Vlahcevic, Z. R., Schwartz, C. C., Gustafsson, J., Danielsson, H. and Swell, L. (1980). Bile acid metabolism in cirrhosis. VI. Sites of blockage in the bile acid pathways to primary bile acids. Gastroenterology. 79 620-628. 

Bile Salts Enable the Digestion of Lipids Cholesterol is the precursor of both steroids and bile salts and is an integral component of cell membranes. It is eliminated from the body via conversion to bile salts and direct secretion into the bile. In fact, the word cholesterol (from the Greek chole (bile) and stereos (solid)) was used originally to describe the material of which gallstones are made. In the process of degradation, it is converted to the primary bile acids cholic acid and chenodeoxycholic acid in approximately equal amounts. The salts of these acids are excreted in bile. They perform two important functions in the digestive tract ... 

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