Bile acids, crystalline structures

Sterols and Cholesterol. Natural sterols are crystalline C76 C1(1 steroid alcohols containing an aliphatic side chain at C17. Sterols were first isolated as lionsaponifiable fractions of lipids from various plant and animal sources and have been identified in almost all types of living organisms. By far, the most common sterol in vertebrates is cholesterol (8). Cholesterol serves two principal functions in mammals. First, cholesterol plays a role in the structure and function of biological membranes.. Secondly, cholesterol serves as a central intermediate in the biosynthesis of many biologically active steroids, including bile acids, corticosteroids, and sex hormones. 

Several prominent types of host molecule, such as the steroidal bile acids and the cyclodextrins, are chiral natural products that are available as pure enantiomers. Chemical modification of these parent compounds provides an easy route to the preparation of large numbers of further homochiral substances. Since all these materials are present as one pure enantiomer, it automatically follows that their crystalline inclusion compounds must have chiral lattice structures. It is not currently possible to investigate racemic versions of these compounds, but the examples discussed previously in this chapter indicate that very different behaviour could result. 

DCA is the first bile acid whose inclusion ability was confirmed in the crystalline state. During the last century many research groups dealt with the inclusion compounds of DCA with various guest molecules, such as aliphatic, aromatic and alicyclic hydrocarbons, alcohols, ketones, fatty acids, esters, ethers, nitriles, peroxides and amines, and so on [2], In 1972, Craven and DeTitta first reported the exact crystal structure of DCA with acetic acid [3], Subsequent crystallographic studies made clear that most of DCA inclusion crystals have bilayer... 

Biochemically, a change in structure relating to the mucopolysaccharides (neuraminic add ) and monohydroxy bile acids probably accounts for the formation of biliary thrombi. Some of the under-hydroxylated bile salts appear in crystalline form the bile becomes increasingly viscous and its flow is impeded. This defect in the excretion of bile salts culminates in dysfunctions in the secretion of bilirubin, which is why bilirubin is regurgitated into the blood. The bile which accmnulates in the bile ducts ultimately becomes mucous and white because of the reabsorption of bile pigments by the epitheha of the small bile ducts. 

This hitherto neglected area is now receiving major attention and the crystalline structures of many common and uncommon bile acids [43,44,48,49], their alkaline and alkaline metal salts [7,51,53] have been defined. Choleic acids have been the subject of much activity in this field. A summary of the earlier work on choleic acids can be found in Sobotka [42] and Small [5]. 

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. 

Several other atypical acids were eventually isolated from various species. Ursodeoxycholic acid, first isolated in crystalline form from bear bile in 1927 (58), was identified as the 7/S-epimer of chenodeoxycholic acid. The so-called /3-hyodeoxycholic acid (3 3,6a), which Kimura obtained in small amounts from pig bile (59), was structurally identified in the course of a thorough investigation of the four possible 3,6-dihydroxycholanic acids (60). The lagodeoxycholic acids isolated from rabbit bile by Kishi (61) were not characterized until the recent studies of Danielsson et al. (62) identified one of these compounds as allodeoxycholic acid. The contention that one of them may have been the 12 -epimer of deoxycholic acid was placed in doubt by Koechlin and Reichstein (63), who prepared that acid and found that it did not exhibit the physical properties of the natural material. 

The crystalline structure of cholanic acids and their alkaline metal salts has unfortunately been neglected. The major crystallographic work was carried oUt by Kratky, Giacomello, and co-workers (76-79) 30 years ago and was oriented toward solving the structure of the choleic acids. These substances, isolated by Wieland and Sorge (80), are mixed crystals of deoxy-cholic acids (or certain other bile acids such as a and apocholic acids) obtained on crystallization from organic solvents. A summary of the work on choleic acid appears in Sobotka (28). 

The structures of certain uncommon bile acids and their ethyl esters have abo been studied (79, 81), and incomplete crystal data of certain bile acid derivatives given in a brief note (72). The crystalline structures of most of the common bile acids and their alkaline salts have not yet been defined. 

In an earlier review [3], mixed micelles formed by bile salts were classified into those with (i) non-polar lipids (e.g., linear or cyclic hydrocarbons) (ii) insoluble amphiphiles (e.g., cholesterol, protonated fatty acids, etc.) (iii) insoluble swelling amphiphiles (e.g., phospholipids, monoglycerides, acid soaps ) and (iv) soluble amphiphiles (e.g., mixtures of bile salts with themselves, with soaps and with detergents) and the literature up to that date (1970) was critically summarized. Much recent work has appeared in all of these areas, but the most significant is the dramatic advances that have taken place in our understanding of the structure, size, shape, equilibria, and thermodynamics of bile salt-lecithin [16,18,28,29,99-102,127, 144,218,223,231-238] and bile salt-lecithin-cholesterol [238,239] micelles which are of crucial importance to the solubihty of cholesterol in bile [1]. This section briefly surveys recent results on the above subclasses. Information on solubilization, solubilization capacities or phase equilibria of binary, ternary or quaternary systems or structures of liquid crystalline phases can be found in several excellent reviews [5,85,207,208,210,211,213,216,217] and, where relevant, have been referred to earlier. 

---