Structure of the Bile Acids

The complete structure of the bile acids was elucidated by H. WiELAND in 1932. 

Bile acid metabolism in conventional animals is the activity of a balanced ecological system composed of the host, the associated intestinal microflora, and the diet. The host contributes the bile acids themselves and serves to maintain the homeostasis of the gastrointestinal tract. The intestinal microflora alters the molecular structure of the bile acids which it comes into contact with and also profoundly alters the physiological and, to a degree, the anatomical features of the host. The diet contributes the nutrition for both the host and the intestinal microflora and can cause marked changes in the flora s activity toward the bile acids in vivo (52). In addition, the amount of dietary sterols may cause the host to change its absorption and/or catabolism of cholesterol to bile acid and thus the rate of bile acid excretion (53). 

With the elucidation of the elementary formula of cholic acid, a number of investigators began to contribute toward the nature of the functional groups. Hoppe-Seyler (16), for instance, showed that cholic acid was a mono-carboxylic acid which yielded a monomethyl or monoethyl ester, that the three remaining oxygen atoms were present as hydroxyl groups and that, under proper conditions, it was possible to obtain the triacetate of methyl cholate (17). The elucidation of the structure of the bile acids was carried out by Wieland and his co-workers, beginning in 1912 (18). 

Surface studies of insoluble monolayers of various bile acids have been studied by several groups, especially those of Ekwall (102-105) and Otero Aenlle (95, 106-110). In Fig. 12 are given the isotherms of some of the bile acids on 3 Af NaCl, 20°C, compiled from the work of Ekwall et al. (102-105). Figure 13 summarizes the important data derived from these isotherms. A diagrammatic representation of the surface structure of the bile acids at the... 

Figure 7.13 shows some of the structures of common bile acids. In low ionic strength solutions, sodium taurocholate forms tetrameric aggregates, with critical... 

Figure 1 Schematic representation of the facially amphiphilic and asymmetric structure of a bile acid, a skeletal structure which can be likened to the body of a turtle.

Most of the bile acid derivatives exhibit guest-dependent polymorphism. The typical host is CA, which forms at least 12 host frameworks, depending on guest sizes and shapes, as shown in Figure 8. Most organic guests form bilayer structures, which can be further classified into several subtypes on the... 

Electrophysiological studies of the smell and taste systems of fish have likewise demonstrated chemoreceptor cells that are responsive, with varying degrees of specificity, to the amino acids known to elicit feeding behavior.73 75 In addition, a number of fish have receptor cells that respond to bile acids, amphipathic steroid compounds that are used as digestive detergents and that can be released into the environment in substantial quantities. Responses can exhibit both exquisite specificity for the structure of a bile acid, and extreme sensitivity, as best exemplified by the sea lamprey.76 77... 

Knowing the fragmentation diagram of the bile acids, i.e. the structures of the fragments produced, allows one to determine the complete structure of the molecule. For example, the masses of fragments A and B indicate the presence or the absence of a hydroxyl group at position C-12. 

Intracellular transport of bile acids mainly takes place through the cytoskeleton and intracellular structures (Golgi apparatus, endoplasmic reticulum). Here, too, cholestatic factors can prove to be damaging. Microfilaments are contractile elements not only is the intracellular transport of the bile acids disturbed, but the peristaltic activity of the canaliculi (so-called paralytic cholestasis within the lolsules) is also reduced if the functional capacity of those microfilaments becomes diminished. 

G. Corsiero, D. Girbig, R Konig, W. Weyland, C. Identification of the Bile Acid-Binding Site of the Beal Lipid-Binding Protein by Photoaffinity Labeling, Matrix-Assisted Laser Desorption Ionization-Mass Spectrometry, and NMR Structure, 7. Biol. Chem. 276,7291-7301 (2001). 

In 1934, Shimizu and Oda isolated a major bile acid from the toad, Bufo vulgaris formosus, which they named trihydroxybufosterocholenic acid [48]. The structure of this bile acid was elucidated in 1967 by Hoshita et al. as 3a,7a,12a-trihydroxy-... 

Bile acids synthesized in the liver are primarily derivatives of 5/S-cholanic acid however, bile acids of lower animals and some fishes may be predominantly of the 5 a or alio series. A significant feature of these two types of bile acids lies in the planar structure of the 5a-acids as opposed to the 5j8-acids where ring A is extended below the planes of rings B, C, and D (Fig. 1). As noted below small quantities of alio acids are now detected from mammalian sources. 

As noted earlier, bile acids were among the first steroids to be obtained in pure crystalline form. These compounds played an important role in the effort devoted to divining the structure of steroids. Bile acids as a result acquired a sizeable number of trivial names, most of which gave little information as to their chemical structure. One approach to systematic names is based on the hypothetical cholanoic acid 8-1 (Scheme 8). Bile acids are then named as derivatives of this structure using the mles used for other classes of steroids. Note the cis A-B ring fusion in this series. The systematic name for 8-2, lithocholic acid, is then simply 3a-hydroxy-5/3-cholanic acid. Chenodeoxycholic acid, 8-3, becomes 3a,7a-dihydroxy-5/3-cholanic acid. The predominant acid in bile, 8-3, is cholic acid itself, or, 3a,7a,12a-trihydroxy-5 )8-cholanic acid. 

Give a comprehensive account of the Bile Acids . How are they isolated from the natural bile Support your answer with the structure of known bile acids. 

Heinrich Otto Wieland (Germany) for his investigations of the constitution of the bile acids and related substances. The bile acids are a set of steroid acids whose synthesis begins in the liver with the production of chloic acid chenodeoxycholic acid (all of which derive from cholesterol). Wieland isolated and determined the structure of a number of these biochemically significant compounds. During his career he also isolated toxins from poisonous frogs and mushrooms. 

The molecular arrangement of the bile acid-lipolytic product micelle is unknown but is probably similar to that of the bile acid-lecithin micelle, the structure of which, based on nuclear magnetic resonance studies, is a cylindrical bimolecular leaflet of lecithin molecules coated on the sides by bile acid molecules, their hydrophobic backs apposed to the paraffin chains of the phosphatide (65). All of the molecular species of the micelle are considered to be in rapid exchange with those of other micelles, as well as the concentration of molecularly dispersed lipolytic products and bile acids (at their CMC) in the bulk phase surrounding the micelles. Benzene molecules exchange rapidly between bile acid-monoglyceride micelles, a mean micellar... 

Figure 2 (Top trace) TIC plot of the TMS derivatives of metabolites of A -tetrahydrocannabinol extracted from mouse liver. Metabolites appear in scans 160-360, fatty acids in scans 0-160, and bile acids in scans 360-480. (Lower trace) Single ion plot of the ion at m/z 145, diagnostic for hydroxylation at a specific site in the drug molecule. The metabolites producing peaks in the region of scans 250-320 contain this structural feature, while the other metabolite-related peaks do not. However, the ion is also present in the spectra of the fatty acids but not in those of the bile acids. The separation used a 2 m SE-30 packed column with a temperature-programmed run (2°min h-...

Cholesterol is a zoosterol that is present in all animal cells. It has a low solubility in water, about 0.2 mg/100 ml. It is the major sterol in human beings and is important as a constituent of various biological membranes, it is particularly important in the myelinated structures of the brain and central nervous system and may constitute up to 170 g/kg. it is the precursor of the steroid hormones, it is also the precursor of the bile acids. 

Lithocholic acid was first isolated from a gallstone by Fischer in 1911 (30). It was later isolated from ox bile (1 g from 100 kg of bile) (64) from rabbit bile (0.4 g from 900 ml) (65) and subsequently from monkey, human, pig, and guinea pig bile (2, 66, 67). Lithocholic acid has been identified as one of the bile acids in human blood (68) and as a principal fecal bile acid. Moset-tig et al. (69) isolated lithocholic acid from human stool and estimated its concentration to be 3 g/100 kg of fresh stool. Lithocholic acid is particularly insoluble, is not hydroxylated to an appreciable extent in man (70), and may be the cause of liver disease (4). In early studies lithocholic acid was not available in sufficient amounts from natural sources and was prepared from cholic acid. Lithocholic acid was particularly valuable in establishing the correspondence of the B/C ring structure between bile acids and cholesterol (71). 

Before attempting a quantitative gas-liquid chromatographic analysis of a bile acid mixture it is for obvious reasons necessary to establish the identity and homogeniety of the compounds (i.e., peaks) eluted from the gas chromatograph. Since identification with classical methods may be tedious and require large amounts of bile acids, the structure of a bile acid often has to be tentatively elucidated by chromatographic methods including derivati-zation procedures. 

Therefore, I shall concentrate on only those bile acids that have been reasonably well studied from a physicochemical point of view and which have some relation to physiology and biochemistry of living things. Because the specific physical characteristics of the bile acids and their alkaline metal salts vary considerably with the number of hydroxyl groups present on the steroid nucleus, I will present a fairly detailed description of the physicochemical properties of cholanic acid (no hydroxyl groups), monohydroxy, dihydroxy, and trihydroxy bile acids. Since the triketo bile acid (dehydrocholic acid) has been used widely as a choleretic, its properties will also be discussed. Unfortunately, many interesting bile acids and bile alcohols isolated from a variety of vertebrates (29-32) have not been studied physicochemical ly. However, knowing their molecular structure, many of the properties of these compounds can be deduced by comparison with the known properties of bile acids discussed in this chapter. 

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