The Bile Alcohols

The bile salts found in vertebrates classified below the level of the reptiles are unique in that they are mostly sulfate esters of polyhydric alcohols. The bile alcohols, such as scymnol (24,25-oxido-3a,7a,12a,26-tetra-hydroxycoprostane), ranol (3a,la, 12a,24,26-pentahydroxy-27-norcholestane), and cyprinol (3a,7a,12a,26,27-pentahydroxycholestane), are discussed in a recent review by Hoshita and Kazuno (53) and in Chapter 2 by Matschiner (this volume). 

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Scynmol, a polyhydroxylated cholestane sterol of the bile alcohol class, isolated from the Arctic shark, Scymnus borealis, is one of the few new metabolites described from Arctic species. It is quite similar to ciprinol, however, isolated from the freshwater carp, Cyprinus carpio (Scheuer 1973). 

The bile alcohol Boymnol, a characteristic constituent of the bik of certain sharks, was at one time believed to contain an epoxide function, as in (XXIX)189 Experimental evidence recently published by Cross 8M 1971 however, has confirmed a suspicion already expressed earlier by Fieser and Fieser8 1 that this alignment was in error. The correct structure of scymnol ia probably (XXX). 

High-performance liquid chromatography (HPLC) of the bile alcohols was carried out on a Waters Associates ALC 201 system employing a Waters model 401 refractive index detector and a Waters 4-mm ID x 30-cm p Bondapak Cjg column (Waters Associates Inc., Milford, MA). The solvent system was 80 % Me0H/H20 (v/v) with a flow rate of 1.5 mL/min. 

This rare inherited hpid storage disease is characterized by xanthomas, progressive neurological dysfunction, cataracts and the development of xanthomatous lesions in the brain and lung. In contrast to other diseases with tendon xanthomatosis, plasma cholesterol levels are remarkably low. Large deposits of cholesterol and cholestanol are present in most tissues, and the concentration of cholestanol is 10-100 times higher than normal. Salen and collaborators have made extensive and elegant studies on the various metabolic aspects of this disease [184,185,187-192]. They have conclusively shown that there is a subnormal synthesis of bile acids and that the metabolic defect is an impaired oxidation of the cholesterol side chain. The synthesis of chenodeoxycholic acid is reduced more than that of cholic acid. These patients excrete considerable amounts of bile alcohol in bile and faeces. The bile alcohols have been identified as 5)S-cholestane-3a,7a,12a,25-tetrol, 5 8-cholestane-3a,7a,12a,24,25-pentol and 5/8-cholestane-3 ,7a,12a,23,25-pentol. Two different explanations for the accumulation of these bile alcohols have been presented. 

Bile alcohols found in lower vertebrates are polyhydric derivatives of cholestane (C27), 27-norcholestane (C26), 26,27-dinorcholestane (C25) or cholane (C24). The trivial names of the bile alcohols include as a prefix part of the Latin name of the genus of the animal from which they were first isolated. When both isomers differing in the configuration at C-5 are known, the prefix 5a or 5)8 is then used with the... 

Bile alcohols and bile acids are steroids with an isoprenoid side chain at C-17 terminated by a CH2OH or carboxy group. The steroid moiety may be hydroxy-lated at different positions, e.g., at C-3bile alcohols may be conjugated with sulfate (D 11) the bile acids, with glycine (D 10) or taurine (D 11.1). 

The analogous compounds with side chains one methylene group shorter and also those with the same number of carbon atoms but variously positioned hydroxyl group in the side chain, can be satisfactorily separated this had been impossible by the column chromatography hitherto available. As far as other structural elements are concerned, the bile alcohols behave just like other steroids (see section IV). Strongly acid reagents like sulphuric acid are employed for visualisation. 

CJH4O5, H02CCH(0H)C02H. Colourless crystals with IH O lost at 60 C. M.p. IhO C (decomp.). Prepared by heating dinitrotartaric acid in aqueous alcohol, taurine, aminoethylsulpbonic acid, C2H7NO3S, NHj CHj CH SOjH. Crystallizes in columns, decomposing at 317 C. In combination with cholic acid it forms one of the bile acids. It is formed in the liver from cysteine. 

Cholesterol is the central compound m any discussion of steroids Its name is a combination of the Greek words for bile (chole) and solid (stereos) preceding the characteristic alcohol suffix ol It is the most abundant steroid present m humans and the most important one as well because all other steroids arise from it An average adult has over 200 g of cholesterol it is found m almost all body tissues with relatively large amounts present m the brain and spinal cord and m gallstones Cholesterol is the chief constituent of the plaque that builds up on the walls of arteries m atherosclerosis... 

Chlordecone and chlordecone alcohol (chlordecol) are excreted in the bile and eliminated via the feces of humans occupationally exposed to chlordecone (Blanke et al. 1978 Boylan et al. 1979 ... 

Cholestyramine use is not without limitations. It does not bind chlordecone alcohol, a metabolite of chlordecone that is also excreted in the bile (Guzelian 1981). It has a gritty texture in the mouth, and it causes several gastrointestinal disturbances, which may limit the willingness of patients to take it. It may also interfere with the absorption of fat-soluble vitamins and interact with other medications (Goldfrank 1990). 

Cholesterol C27H45OH, an unsaturated secondary alcohol, contains the same ring system as the bile acids and is closely related to them genetically. Pseudocholestane, indeed, which is a stereoisomer of the parent hydrocarbon of cholesterol, cholestane, can be oxidised to cholanic acid by chromic acid with elimination of acetone (Windaus). 

All of the above examples are acetates of active alcohols. Here, we also mention the acetate of a phenol, namely the provitamin a-tocopheryl acetate, whose natural enantiomer of absolute configuration (2R,47 ,87 ) is shown as 8.73. a-Tocopheryl acetate is a substrate of cholesterol esterase (EC 3.1.1.13), and was hydrolyzed in rats faster than its (2S,47 ,87 )-epimer. In vitro experiments required a-tocopheryl acetate to be dispersed as a micellar pseudosolution, and the nature of the bile salt used to prepare micelles had a profound effect on the substrate stereoselectivity of the reaction [95] [96], Only when the micelle composition approximated that of the gastrointestinal tract did the in vitro substrate stereoselectivity resemble that seen in vivo. 

Itching associated with retention of bile acids is ameliorated by treatment with the bile acid binding resin cholestyramine. Fat soluble vitamin (A, D and K) deficiency may require administration of supplements. Direct toxic effects of alcohol associated with dietary deficiency may require soluble B vitamin administration. 

Allyl chloride is presumed to be metabolized to allyl alcohol, which could then be further metabolized via two pathways to form either acrolein or glycidol, from which a variety of metabolites could result. Metabolites identified in rat urine are 3-hydroxy-propylmercapturic acid and allyl mercapturic acid and its sulfoxide. Allyl glutathione and S-allyl-L-cysteine have been detected in the bile of dosed rats. In-vitro metabolism of allyl chloride results in haem destruction in microsomal cytochrome P450 (lARC, 1985). 

Reduction of ketones. Reduction of ketones with metals in an alcohol is one of the earliest methods for effecting reduction of ketones, and is still useful since it can proceed with stereoselectivity opposite to that obtained with metal hydrides.1 An example is the reduction of the 3a-hydroxy-7-ketocholanic acid 1 to the diols 2 and 3. The former, ursodesoxycholic acid, a rare bile acid found in bear bile, is used in medicine for dissolution of gallstones. The stereochemistry is strongly dependent on the nature of the reducing agent (equation I).2 Sodium dithionite and sodium borohydride reductions result mainly in the 7a-alcohol, whereas reductions with sodium or potassium in an alcohol favor reduction to the 7p-alcohol. More recently3 reduction of 1 to 2 and 3 in the ratio 96 4 has been achieved with K, Rb, and Cs in f-amyl alcohol. Almost the same stereoselectivity can be obtained by addition of potassium, rubidium, or cesium salts to reductions of sodium in t-amyl alcohol. This cation effect has not been observed previously. 

MIESCHER DEGRADATION. Adaptation of the Barbier-Wieland carboxylic acid degradation to pcrmil simultaneous elimination of three carbon atoms, as in degradation of the bile acid side chain to the methyl ketone stage. Conversion of the methyl ester of the bile acid to the tertiary alcohol, followed by dehydration, bromination. dehydrohalogenatinn, and oxidation of the diene yields die required degraded ketone. 

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