Lithocholic acid, structure

Lithocholic acid, structure of, 1082 Locant, IUPAC naming and, 87 Lone-pair electrons, 9 Loratadine, structure of, 206 Lotaustralin. structure of. 766 Low -density polyethylene, synthesis of, 1210... 

The isolate appears to produce the enzymes for the complete catabolism of lithocholic acid. However, in the presence of Pb2+ ions, some of these catabolic enzymes are inhibited, leading to the accumulation of partial breakdown products. It appears that enzymes involved in catabolism of the ring structure are more susceptable to inhibition by Pb2+ ions than are the enzymes involved in side chain catabolism. 

Bile Acids and Alcohols. Bile acids have been detected in all vertebrates that have been examined and are a result of cholesterol metabolism. The C24 acid, 5(8-cholatiie acid (9) is the structural derivative uf the majority of bile acids in vertebrates. Most mammalian bile acids have a cis-fused A-B ring junction resulting in a nonplanar steroid nucleus. Bile acids, like sterols, typically contain a C3a-hydroxyl group (lithocholic acid 3a-hyroxycholanic acid. 

The second approach was applied in the synthesis of fatty acid terminated polyanhydrides. Polyanhydrides based on sebacic acid, and terminated with oleic, stearic, linoleic or lithocholic acid, or combinations of several fatty acids were synthesized 21). The general structure of fatty acid terminated polyanhydrides is shown in Figure 1. 

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 ... 

Synthesis and characterization of lithocholic acid derived dipyrromethanes. Koivukorpi et aO in early 2004 reported the synthesis of a series of steroidal dipyrromethane analogues that can be exploited for the synthesis of pyrrole-steroidal macrocycles. The authors used long-range HMBC data to confirm the structure. 

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). 

Other precursors of the muricholates via 6)8-hydroxylation include 5)8-cholanic acid [78], lithocholic acid [84-86], 7-oxolithocholic acid [95,96], and ursodeoxycholic acid (3a,7j6-dihydroxy-5/3-cholanic acid) [97], The rat metabolized 12a-hydroxy-5/S-cholanic acid to 6/S,12a-dihydroxy-5)S-cholanic acid [83] and a small amount of 6)3,7a,12a-trihydroxy-5 -cholanic acid [98]. 3a,6)8,12a-Trihydroxy-5)8-cholanic acid was isolated from urine of surgically jaundiced rats after administration of de-oxycholate [99]. A series of bile acids from rat bile of unconfirmed structures but containing the 6/3,7/3-diol will be reviewed in Section II1.3. 

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. 

Base peak in 7a-hydroxy-cholesterol Base peak in 3p,7a-dihydroxy-A -C24 Intense ion in 3,7P-dihydroxy structure Base peak in 6-oxo-lithocholic acid Base peak in 3p,7a-dihydroxy-5-cholestanoate... 

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). 

Mizushina Y, Ohkubo T, Sugawara F, Sakaguchi K. (2000) Structure of lithocholic acid binding to the N-terminal 8-kDa domain of DNA polymerase p. Biochemistry 39(41) ... 

Mizushina Y, Kasai N, Sugawara F, lida A, Yoshida H, Sakaguchi K (2001) Three-dimensional structural model analysis of the binding site of lithocholic acid, an inhibitor of DNA polymerase P and DNA topoisomerase II. J Biochem 130(5) 657-664... 

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 cholestatic properties of monohydroxy bile acids, especially of lithocholic acid, are well established in experimental animals. Intravenous administration of lithocholic acid and its taurine or glycerine conjugate to rats or hamsters causes a dose dependent reduction in bile flow[l,2,3,4], associated with specific ultra-structural and biochemical changes in the bile canalicular membrane and pericanalicular region[5,6,7]. Lithocholic acid is a normal albeit only a minor constituent of normal human bile and serum[8]. 

The most prominent BA present in human are cholic acid (C), chenodeoxy-cholic acid (CDC), deoxycholic acid (DC), lithocholic acid (LC), and ursodeoxycholic acid (UDC), as derivatives of 5p-cholan-24-oic acid. Primarily they are present as glycine and taurine conjugates, with the conjugation occurring at carbon 24 of the structure. In addition to the above major BA, a wide array of minor components has been identified. 

Although the list of polymerizable terpene alkenes in Fig. 1 may, for whatever reason, not be complete, a large number of native terpenes remain that cannot be submitted to any kind of controlled chain-growth polymerization process. Terpenes may eventually be converted into polymerizable monomers, as has for instance been demonstrated for menthone, carvone, and bile acids, i.e., cholic acid and lithocholic acid (see the structures in Fig. 4). 

Fig. 4 Chemical structures of (a) menthone, (b) carvone, (c) cholic acid, and (d) lithocholic acid...

Scheme 11 (a) Structures of bile acids and (b) synthesis of polyanhydiide liom dimers of lithocholic acid [110] (reproduced with permission fixjm American Chemical Society)... 

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). 

FIGURE 3.4 Structures of endogenous compounds involved in glucuronidation bile adds, lithocholic add (LA) and hyodeoxycholic acid (HDCA) short chain bile acids, etianic add and isoetianic add, steroid hormones, androsterone, testosterone, estrone, estradiol, estriol. 

The dehydration of desoxycholic acid (33) yielded a diene mixture that could be hydrogenated to cholanic acid (34). Wieland and his co-workers also showed that both lithocholic and chenodesoxycholic acids were related to cholanic acid (35, 36). The positions and configurations of the hydroxyl groups were determined in the course of a series of oxidative cleavage studies, which actually bore upon the question of the ring structure. 

Summary of the Structural Information Obtained from Infrared Spectra In crystals of cholanic (A), lithocholic (B), and dehydrocholic (F) acid, the predominant mode of intermolecular association is that of the carboxylic... 

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