Bile acids, secondary deoxycholic acid

It seems to be a general observation that the proportion of chenodeoxy-cholic acid is increased in liver cirrhosis. Thus the ratio cholic acid/cheno-deoxycholic acid has been found to be decreased in the bile (23), serum (52,134,193,195-198), and urine (88,199) of cirrhotic subjects. Since the ratios of cholic acid, chenodeoxycholic acid, and deoxycholic acid appear to be approximately the same in bile and serum (200,201), and perhaps also in urine, it seems quite obvious that the bile acid pattern in any of these three sources is similar to that produced by the liver. Simultaneous determinations of bile acids from bile, serum, and urine have not been made, however. The relative increase of chenodeoxycholic acid has been interpreted to indicate a hindrance of 12a-hydroxylation in liver injury when the formation of cholic acid is decreased in favor of chenodeoxycholic acid (202). This, on the other hand, changes the pattern of secondary bile acids so that relatively more lithocholic acid is formed in the colon (191,200,202), the amount of deoxycholic acid being reduced (23,52,134,193,195-198), particularly because quantitatively only a small portion of the bile acids escapes daily from the ileum to the colon (23). 

In this model the secondary bile acid sodium deoxycholate appears to be neither tropic nor co-carcinogenic to hypoplastic defunc-tioned colon. The previously cited experiment showing that bile and pancreatic juice could stimulate adaptive mucosal hyperplasia and carcinogenesis after surgical diversion involved distal gut remaining in continuity with the faecal stream[29]. Thus any effect of bile acids in promoting colorectal neoplasia or in maintaining mucosal cell turnover is likely to depend in part on other luminal factors. 

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. 

Bile acids within the enterohepatic circulation that undergo absorption in the terminal ileum encounter a relatively low number of species and population of bacteria and return to the liver in portal blood relatively unchanged. However, the approximately 5% of the bile-acid pool that enters the colon provides substrate for the extensive microbial population that deconjugate and oxidise hydroxyl groups leading to formation of the secondary bile acids deoxycholic and lithocholic acids that are the major bile acids in faeces. 

Micromolar quantities of RNS are generated primarily by nitric oxide synthase 2 (NOS2), an enzyme that is up-regulated during colon-cancer progression. As discussed below, deoxycholate (DOC), a hydrophobic secondary bile acid, activates the redox-sensitive transcription factor NF-kB, resulting in increased levels of NOS2 and enhanced S-nitrosylation of proteins. Additional sources of bile-acid-induced ROS and RNS are also likely. ... 

Jenkins et al. demonstrated that the secondary bile acid, deoxycholic acid could induce micronuclei formation in the oesophageal adenocarcinoma cell line, OE33. The induction of micronuclei demonstrated a dose-dependent effect and occurred under both neutral and acidic pH conditions. An example of a micronucleus induced by treatment of the OE33 oesophageal adenocarcinoma cell line with deoxy cholic acid is shown in Figure 4.3. 

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.

P. K. Baijal, D. W. Fitzpatrick and R. P. Bird, Comparative effects of secondary bile acids, deoxycholic and lithocholic acids, on aberrant crypt foci growth in the postinitiation phases of colon carcinogenesis, Nutr. Cancer, 1998, 31, 81. 

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. 

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). 

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... 

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. 

The secondary bile acids become partially (30-50%) absorbed in the intestine and, following reconjugation with glycine or taurine in the liver, are excreted into the canaliculi. The bile thus contains a mixture of primary and secondary bile acids. Deoxycholic acid as a secondary bile acid is likewise an end-product it enters the enterohepatic circulation without further modification. Conjugation of the secondary bile acids in the liver yields the following four conjugated bile acids ... 

Particularly efficient solubilizing agents of the bile acid family are the salts of deoxycholic acid 6". Their complexes with water-insoluble compounds are called choleic acids . The aggregation number of deoxycholic acid (DCA) in distilled water is approximately 10-12 ( primary micelles ) and rises to about 100 ( secondary micelles ) in more concentrated solutions and/or after addition of electrolytes to primary micelles. The cmc of primary micelles lies in the range of 1-5 x 10 mol/L. Less polar cholic acids are in general much better... 

The two bile acids, cholic acid and chenodeoxycholic acid, which are synthesized from cholesterol in the liver, are termed primary bile acids. Each day, around one-third to one-quarter of the primary bile acid pool is lost or converted to secondary bile acids by anaerobic bacteria in the intestine. This is achieved by 7a-dehydroxylation, a process which converts cholic acid to deoxycholic acid (3a,12a-dihydroxy-5p-cholan-24-oic acid) and chenodeoxycholic acid into lithocholic acid (3a-hydroxy-5 -cholan-24-oic acid). 

Expression of IBABP and ASBT is regulated by the famesoid X receptor (FXR), a nuclear orphan receptor (246, 247). A specific binding site for F3 was found on the promotor region of the IBABP gene, named bile acid response element (BARE) (248). The response was greatest in the presence of chenodeoxy-cholic acid (CDCA), whereas cholic acid was much less effective and the secondary bile acids deoxycholic and lithocholic acid had variable responses. 

Quantitatively, the most important bile acid microbial transformation of cholic and chenodeoxycholic acid is the 7a-dehydroxylation yielding the secondary bile acids deoxycholic acid and lithocholic acid, respectively. The 7 -dehydroxylation alters markedly the physical properties and physiological effects of the bile acid molecule. There is a decrease in the solubility of secondary bile acids in aqueous solutions and an alteration of the critical micellar concentration (Chapter 13). 

Lastly, mention should be made of a recent study of the possible co-carcinogenic effects of bile salts in which enhanced uptake by the colon of 7,12-dimethylbenzanthracene was demonstrated in the presence of deoxycholic add [114]. It is very likely that this reflects an increase in mucosal permeability caused by this secondary bile acid. 

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