Chenodeoxycholic acid structure

Therapeutic Function Solubilizer for cholesterol gallstones Chemical Name 3,7-Dihydroxycholan-24-oic acid Common Name Chenodeoxycholic acid chenic acid Structural Formula ... 

Figure 4.14 Structures of cholic and chenodeoxycholic acids which are the acids that form the bile salt The asterisk indicates the position at which an ester bond is formed with taurine or glycine so that bile salts are taurocholate, chenodeoxytaurocholate, gly-cocholate, and glycochenodeoxycholate are formed. The structure of taurine is H2NCH2CH2SO3 and glycine is H2NCH2COOH.

Fig. 5.4.1 Chemical structures of bile acids (BAs) (reprinted from [2]). CA Cholic acid, CDCA chenodeoxycholic acid,...

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. 

The bile acids are produced in the liver by the metabolism of cholesterol. They are di- and trihydroxylated steroids with 24 C atoms. The structure of cholic acid was seen earlier (Sec. 6.6). Deoxycholic acid and chenodeoxycholic acid are two other bile acids. In the bile acids, all the hydroxyl groups have an a orientation, while the two methyl groups are /3. Thus, one side of the molecule is more polar than the other. However, the molecules are not planar but bent because of the cis conformation of the A and B rings. 

The tertiary bile acids are formed in the liver as well as in the gut. (s. fig. 3.3) Intestinally absorbed lithocholic acid is enzymatically converted to sulpholitho-cholic acid in the liver. Ketolithocholic acid is transformed to (hypercholeretic) ursodeoxycholic acid in both the intestine and the liver. When passing through the canaliculi, UDC is partly reabsorbed by epithelial cells and returned to the liver via the blood circulation (= cholehepatic shunt). (41) The latter is chemically and structurally identical to chenodeoxycholic acid, of which it is deemed to be the 7P-epimer ... 

Bile acids contain hydroxyl groups, which are usually substituted at positions, C-3, C-7, or C-12 of the steroid nucleus. The three major bile acids found in man are 3a,7a,12a-trihydroxy-5P-cholan-24-oic acid 3a,7a-dihydroxy-5p-cholan-24-oic add and 3a,12a-dihydroxy-5p-cholan-24-oic acid. Because of the complexities of steroid nomenclature, bile acids are nearly always referred to by trivial names. 11108, the three major human bile acids are named cholic acid, chenodeoxycholic acid, and deoxycholic acid, respectively, and their chemical structures are shown in Fig. 1. Human bile does, however, contain small amounts of other bile acids, such as lithocholic acid (3a-hydroxy-5P-cholan-24-oic add) and ursodeoxycholic add (3a,7p-dihydroxy-5p-cholan-24-oic acid) (see Fig. 1). 

The bile acids cholic acid and chenodeoxycholic acid are synthesized from cholesterol in the liver (Dl, S3). Several structural modifications are necessary to convert cholesterol, with its 27 carbon atoms, C-5,6 double bond and 3p-hydroxyl group, to a 24-carbon atom, saturated, 3,7 and 12a-hydroxyl-ated bile acid. The major reactions in this transformation are shown in Figs. 3 and 4. The reactions are catalyzed by mitochondrial, microsomal, soluble, and possibly peroxisomal enzymes. 

In a study by Ali and Elliott it was shown that 5a-cholestane-3 ,7a-diol was an even better substrate for the 12a-hydroxylase in rabbit liver microsomes than 7a-hydroxy-4-cholesten-3-one (156%) [104]. This reaction is probably of importance in the formation of allocholic add. The high specificity of the 12 -hydroxylase towards the coplanar 5a-sterol nucleus is also evident from the finding that allochenodeoxycholic acid can be converted into allocholic acid in rats, both in vivo and in vitro [105,106, Chapter 11]. Based on the known structural requirements of the 12a-hydroxylase, Shaw and Elliott prepared competitive inhibitors with different substitutions in the C,2 position [107]. The best inhibitor of those tested was found to be 5a-cholest-ll-ene-3a,7 ,26-triol. Theoretically, such inhibitors may be used to increase the endogenous formation of chenodeoxycholic acid in connection with dissolution of gallstones. 

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. 

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 primary bile acids are defined as those formed from cholesterol in the liver. Secondary bile acids are those formed from the primary bile acids through the action of intestinal microorganisms during the enterohepatic circulation of bile acids. The secondary bile acids may be subjected to further structural modifications by liver enzymes. The main primary bile acids in most mammalian species are cholic acid and chenodeoxycholic acid.t Other... 

The structural changes involved in the conversion of cholesterol into chenodeoxycholic acid are the same as those in the formation of cholic acid with the exception that no 12a-hydroxyl group is introduced. It has been shown that the mechanisms of conversion of the zl -3i5-hydroxy configuration of cholesterol into the 3a,7a-dihydroxy-5/5 configuration of chenodeoxycholic acid are the same as those in the formation of cholic acid. Similarly, the mechanisms of oxidation of the side chain are the same for chenodeoxycholic acid and cholic acid. Whereas it is now possible to formulate a few probable sequences for these events in cholic acid formation, available information... 

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 23-hydroxy derivative of chenodeoxycholic acid was isolated very early by Hammarsten from seal and walrus bile (137, 138). It was characterized by Windaus and van Schoor in 1928 (139) and the structure confirmed by Bergstrom et al. (140) and Haslewood (136). Originally the acid described here as phocaecholic acid was referred to as /3-phocaecholic acid. It has been found in all Pinnipedia that have been examined and not in other animals. The a-acid also isolated by Hammarsten was subsequently identified by Bergstrom et a . (140) as a tetrahydroxycholanic acid. 

The structure of hyocholic acid was proposed by Haslewood (24) and by Ziegler (7) to be 3a,6a,7 -trihydroxy-5 -cholanic acid (I, Fig. 1). Since it was known that pig bile contains hyodeoxycholic acid (3a,6a-dihydroxy) and chenodeoxycholic acid (3a,7a-dihydroxy) the bile was assumed to contain possibly also an acid with both 6a- and 7a-hydroxyl groups. Chemical evidence for the vicinal glycol structure in hyocholic acid was found after chromic oxidation. The product, 3-keto-6,7-secocholanic acid-6,7-dioic... 

The most important end products in mammalian cholesterol metabolism are the bile acids. The parent C24-acid is cholanic acid with a ring structure identical to that of coprostanol (A/B cis). The bile acids are hydroxylated cholanic acids, all hydroxyl-groups have a-orientation. Consequently, they do not form digi-tonides. The principal acids are cholic acid (3a, 7a, 12a-trihydroxy-cholanic acid), chenodeoxycholic acid (3a, 7a-dihydroxycholanic acid) and deoxy-cholic acid (3a, 12a-dihydroxycholanic acid). Lithocholic acid (3a-hydroxycholanic acid) also occurs in human bile, but only in small amounts. 

The main bile acids present in man, rat, rabbit, and pig are illustrated in Fig. 4. All occur as taurine or glycine conjugates. Hydroxyl functions are found at one or more of the following positions 3a. 6a. 7a, and I2a. The 6a-hydroxylated structures appear thus far to be exclusive for the pig whose bile acids consist in major of chenodeoxycholic and hyocholic acids. 6j3-Hydroxylated acids are only formed to a minor extent. The 7/5-hydroxylated derivative isolated after the administration of chenodeoxycholic acid to the rat (Hsia et al., 1958) has been shown through experiments with a C-7j8 tritiated structure to arise through the inversion of the 7a-hydroxy isomer via the keto structure (Bergstrom et al., 1960b). 16a-Hydroxylated acids have been isolated from boas and pythons but not from a variety of other species of snakes examined (Hazlewood, 1959). The most recent references to pertinent studies are listed in Table I. 

The effects on the dynamics of photo-injected electrons where not systematically studied, despite scattered reports on the influence of amines, which induce surface deprotonation, and lower surface charge with a resulting negative shift in band edge position and an increase in the open circuit potential, Voc [103], The opposite effect is induced by Li+ ions, which intercalate in the oxide structure. Guanidinium ions increase Voc when used as counterions in place of Li+. Other adsorbing molecules that influence both Voc and short circuit current are polycar-boxylic acids, phosphonic acids, chenodeoxycholate and 4-guanidinobutyric acid. 

The liver, and also bacteria in the small and large intestine, can cause other structural modifications to bile acids as they undergo their entero-hepatic cycle. The formation of sulfate esters, already mentioned with respect to lithocholate in Section 4.2.1, is carried out primarily in the liver in man by a sulfotransferase (Lll). Other bile acids can also be sulfoconjugated to a small extent, mainly at the 3a-hydroxyl position. Bacteria, which have been isolated anaerobically from human feces, are known to possess bile acid sulfatase activity, which removes the 3a-sul te group of chenodeoxycholic and cholic acids (H24). The action of this bacterial enzyme probably explains why only trace amounts of sul ted bile acids, which are poorly absorbed in the intestine, are detected in the feces (12). Another type of bile acid conjugate, which has been identified in the urine of healthy subjects and patients with hepatobiliary disease, is the glucuronide (A7, S41). Both the liver and extrahepatic tissues, such as the kidney and small intestinal mucosa, are capable of glucuronidation of bile acids in man (M14). 

Structures of the most common bile acids in human bile cholate and chenodeoxycholate. 

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