Chenodeoxycholic add

FXR is activated by endogenous bile acids such as chenodeoxycholic add. Other known agonists include farnesol, GW4064 with an EC50 of 70 nM, or AGN-31 (Chart 14.5) [12]. 

Functioning as detergents, hydrophobic (Hpophiiic) bile acids (cholic add, chenodeoxycholic add, deoxychohc add, hthochohc acid) exert toxic efifects on the biomembranes of liver cells and mitochondria. At the same time, these bile acids display an immunosuppressive elfect and influence the humoral and cell-mediated defence (e.g. inhibition of monocytes). As in the case of PBC, hydrophobic bile acids also induce an excessive expression of MHC-I and MHC-II molecules from hepatocytes and bihary cells. 

The apical localized sodium-dependent bile add transporter (ASBT) is expressed in the human duodenum and ileum and is barely detectable in colon [16]. ASBT transports bile adds such as glycodeoxycholate and chenodeoxycholic add (XX) [49, 50]. Few examples exist where the bile acid scaffold has been used as a promoiety for a prodrug approach. ASBT has micromolar affinities for the natural substrates, and the studies on ASBT are too few to make a general statement on the potential and role of this transporter in drug absorption [49, 50]. 

Cholic acid differs from chenodeoxycholic acid in having an extra hydroxyl group at C-12. The enzyme responsible for producing this difference, 7a-hydroxy-4-cholesten-3-one 12a-hydroxylase, thus acts at a key branch point in the biosynthesis of bile acids and might be expected to be regulated in order to control the relative amounts of cholic acid and chenodeoxycholic acid produced. Like other hydroxylation steps in bile acid biosynthesis, 12a-hydroxylation requires a specific form of cytochrome P-450, which is present in the cytochrome P-45OLM4 fraction of rabbit liver microsomes (H6). The activity of I2a-hydroxylase has been postulated to be decreased in patients with liver cirrhosis to explain the low proportion of cholic add relative to chenodeoxycholic add in the bile of these patients (V9). Conversely, the activity of this enzyme may be high in patients with cerebrotendinous xanthomatosis, as the bile of these individuals contains mostly cholic acid... 

S2). More recent studies have shown that patients with cirrhosis are able to efficiently convert 7a-hydroxy-cholesterol into cholic acid (G8, P8), suggesting that 12a-hydroxylase activity is near normal. Other evidence from in vivo studies in man with labeled preciusors suggests that 12a-hydroxylase activity is not important in the regulation of the ratio between cholic acid and chenodeoxycholic add in human bile (B21). The possibility that different pools of cholesterol are utilized for the biosynthesis of cholic acid and chenodeoxycholic acid is now being investigated. 

The major pathway for the formation of chenodeoxycholic add is thought to be the same as that for cholic acid, with the exception that no 12a-hydroxylation occurs. Thus, 3a,7a-dihydroxy-5i8-cholestan-26-oic acid is a probable intermediate, and Hanson has shown that this acid can be made from cholesterol and is effidently converted to chenodeoxycholic acid but only to a very limited extent to cholic acid [131]. 

Gonfalves P, Catarino T, Gregorio I, Martel F. Inhibition of butyrate uptake by the primary bile salt chenodeoxycholic add in intestinal epithelial cells. / Cell Biochem. 2012 113 2937-2947. 

The chief bile acids are the taurine and glycine derivates of dwlic add (3a, 7a, 12a-trihydroxycholanic acid), of deoxycholic add (3a, 12a-dihydroxycholanic acid), and of the isomeric chenodeoxycholic add (3a,7a-dihydroxycholanic acid). The bile acids are one of the end products of the metabolism of cholesterol however, over 90% of the amount secreted (20-30 gm per day) is reabsorbed in the intestine and thus stays in the enterohepatic circulation. 

Sutherland, J.D., LA. Macdonald, and T.P. Forrest, The enzymic and chemical synthesis of ursodeoxycholic and chenodeoxycholic add from cholic acid. Prep. Biochem., 1982. 12(4) 307-321. 

Primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA), are synthesised via the 5/3-saturation of the cholesterol double bond by enzymes of the hepa-tocyte microsomal fraction, epimerisation of the 3/j-hydroxyl group to the 3a-con-figuration, and further insertion of a 7 -hydroxyl group, with or without a further 12a-hydroxyl group. After shortening of the side chain by three carbons, oxidation of the terminal carbon of the side chain occurs to form the carboxylic group [3]. Alternative metabolic sequences add to the complexity of this metabolic pathway (Fig. 5.4.2). 

The C>4 bile acids arise from cholesterol in the liver after saturation of the steroid nucleus and reduction in length of the side chain to a 5-carbon add they may differ in the number of hydroxyl groups on the sterol nucleus. The four acids isolated from human bile include cholic acid (3,7,12-tiihydroxy), as shown in Fig. 1 deoxycholic acid (2,12-dihydroxy) chenodeoxycholic acid (3,7-dihydroxy) and lithocholic acid (3-hydroxy). The bile acids are not excreted into the bile as such, but are conjugated through the C24 carboxylic add with glycine or... 

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). 

Samuelson, K., Aly, A., Johansson, C., and Norman, A., Serum and urinary bile adds in patients with primary biliary cirrhosis. Scand. J. Gastroentend. 17, 121-128 (1982). Samuelson, K., and Eklund, A., Determination of urinary cholic and chenodeoxycholic acid conjugates with radioimmunoassay. Scand. J. Clin. Lab. Invest. 40,555-561 (1980). 

Scbalm, S. W., Van Berge Henegouwen, G. P., Hofmann, A. F., Cowen, A. E., and Turcotte, J., Radioimmunoassay of bile adds Development, validation, and prelimiiuuy application of an assay for conjugates of chenodeoxycholic acid. Gastroenterology 73, 285-290 (1977). 

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. 

Bile acids in meconium also reflect atypical synthesis. Back and Walter [209] reported on the presence of 14 bile acids obtained from meconium of 6 healthy infants (Table 2B). On the average 21% of chenodeoxycholate and of hyocholate and 8% of cholate were sulfated. Deoxycholate was the major bile acid of the sulfate fraction lithocholate, 3/8-hydroxy-5-cholenate [175] and 3, 12a-dihydroxy-5-cholenate were found only in the sulfate fraction, but quantities of lithocholate (range 0.3-1.4%) and 3i8,12a-dihydroxy-5-cholenate were small. The amount of l, 3tt,7a,12a-tetrahydroxy acid (79% as the taurine conjugate and 21% unconjugated) ranged from 3.6 to 11.1% of the total bile acids [209]. The feta bile adds of a number of animals, normal, adrenalectomized, thyroidectomized, or diabetic, are reviewed by Subbiah and Hassan ]210]. 

ND, not determined C, cholic acid CDC, chenodeoxycholic acid UDC, ursodeoxycholic add A, 3a-hydroxy-5y8-chol-6-enoic acid. 

Bile acids can also be converted into phenacyl [81] and p-bromophenacyl [102] esters. A bile acid sample with 50% excess of 0.15 M triethylamine in acetonitrile was warmed briefly and 0.1 M phenacyl bromide (50% molar excess) in acetonitrile was added. The reaction mixhire was maintained at 80—90°C for 45—60 min. The separation of phenacyl esters of lithocholic, deoxy-cholic, chenodeoxycholic, ursodeoxycholic hyodeoxy-cholic and cholic acids was carried out on an ODS column. The excess derivatizing agents and interfering biological compounds from bile samples were first eluted with n-heptane/dioxane (90 10 v/v), and the separation of derivatives of bile adds was accomplished with n-heptane/dioxane/isopropanol (70 25 5, by vol). The detection limits at 254 nm for the derivatives were 5-lOng [81]. 

Lithocholic acid 3a-hydroxy-5P-cholanoic add, or 3a-hydroxy-5p-cholan-24 c acid, M, 376.58, m.p. 185 C, [a]D + 32 ° (ethanol). L. a. is a monohydroxyla-ted steroid carboxylic add, and one of the bile acids. It has been isolated from the bile of man, cow, rabbit, sheep and goat, and is normally prepared from bovine bile. L.a. is formed from chenodeoxycholate by intestinal bacteria. It is absorbed and returned to the liver for secretion. It is not readily conjugated, and it is relatively toxic to the liver. L.a. may be important in the pathogenesis of liver damage following biliary sta-... 

Chenodeoxycholic and ChoHc adds (taurine and gtydne conjugates ... 

The main bile adds are cholic acid and chenodeoxycholic acid (3-126). These acids are excreted from the liver as glycine salts or taurine conjugates (see Section 5.15) into the gallbladder and then into the small intestine. In the duodenum, bile adds act as emulsifiers in the absorption and digestion of fats and fat soluble vitamins. 

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