Bile acids dihydroxy

The first studies of specificity were carried out using cholate, the glycine and taurine conjugates and taurine conjugates of the dihydroxy bile acids cheno-deoxycholate and ursodeoxycholate. Kramer and colleagues prepared plasma membrane vesicles from rat liver and compared bile-acid transport with values from CHO cells stably expressing NTCP. This work established that transport by the liver enzyme was maximal when 2 hydroxyls were present,... 

Hormones and vitamins also play a role in regulation of ASBT. Both glucocorticoid receptor ligands and co-expression of the glucocorticoid receptor gene increased activity of ASBT, while there is also evidence that dihydroxy vitamin D binds directly to the vitamin D response element and increases expression of ASBT, leading to increased transport of bile acids into the enterocyte. ... 

Currently available BAS include cholestyramine, colestipol and colesevelam hydrochloride (colestimide). Cholestyramine comprises a long-chain polymer of styrene with divinylbenzene trimethylbenzylammonium groups, whereas colestipol is a long-chain polymer of l-chloro-2,3-epoxypropane with diethylenetriamine. Colesevelam HCl is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and 6-bromo-hexyl-trimethylammonium bromide. Bile-acid binding is enhanced and stabilised in the latter compound by long hydrophobic sidechains, increased density of primary amines, and quaternary amine sidechains. For this reason, colesevelam HCl exhibits increased affinity, specificity and capacity to bind bile acids compared with the other BAS. Colesevelam HCl also binds dihydroxy and trihydroxy bile acids with equal affinity, contrasting with cholestyramine and colestipol that preferentially bind dihydroxy bile acids (CDCA and deoxycholic acid). The latter BAS can lead to an imbalance towards trihydroxy bile acids and a more hydrophilic bile-acid pool. 

Peroxisomal disorders (Zellweger syndrome, Refsum s disease, neonatal adre-noleukodystrophy) are characterised by defective peroxisome biogenesis, or, being present, peroxisomes lacking / -oxidative enzymes. In the BA biosynthetic pathway, dihydroxycoprostanic acid (DHCA) and trihydroxycoprostanic acid (THCA) are /1-oxidised in peroxisomes to produce CA and CDCA, respectively, whereas peroxisomal disorders cause a defective oxidation of the BA precursor side chain, which leads to an accumulation of C27 bile acids, notably 3 ,7 -dihydroxy-5/3-cholesta-noic acid (DHCA) and 3a,7a,12a-trihydroxy-5/l-cholestanoic acid (THCA), in the plasma and urine of affected patients. 

Carey JB (1958) The serum trihydroxy/dihydroxy bile acid ratio in liver and biliary tract disease. J Clin Lab Invest 17 1494-1497... 

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... 

In the bile acid series, lithocholic acid (3) has been converted into 3x,12/ -dihydroxy-5/ -choIan-24-oic acid (4) by the fungus Helicostylum piriformez3q. 

Abnormalities of Bile Acid Delivery to the Bowel. Decreased bile flow from intrahepatic cholestasis or extra-hepatic bUe duct obstruction caused by bUiary atresia, stricture, stone, or carcinoma will result in bile acid retention and regurgitation from the liver ceU into plasma and a decrease in delivery to the intestine. The ratio of plasma trUiydroxy to dihydroxy acids increases in cholestasis. 

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). 

There is a wide variety in the types of bile acids found in different animal species. Some species have unique bile acids, such as a-muricholic acid (3a,6p,7a-trihydroxy-5p-cholan-24-oic add) and -muridiolic add (3a,6, 7 -trihydroxy- -cholan 24-oic acid) in rats and mice, and hyodeoxycholic acid (3a,6a-dihydroxy-Sp-cholan>24-oic acid) in pigs. Haslewood (H9) has studied the distribution of bile acids in the animal kingdom and has suggested that the C-24 adds, which are common to most advanced animal forms, can be regarded as the present endpoints in the evolution of the chemical structure of bile adds. 

The two bile acids, cholic acid and chenodeoxycholic acid, which are synthesized from cholesterol in the liver, are termed primary bile acids. Each day, around one-third to one-quarter of the primary bile acid pool is lost or converted to secondary bile acids by anaerobic bacteria in the intestine. This is achieved by 7a-dehydroxylation, a process which converts cholic acid to deoxycholic acid (3a,12a-dihydroxy-5p-cholan-24-oic acid) and chenodeoxycholic acid into lithocholic acid (3a-hydroxy-5 -cholan-24-oic acid). 

Ursodeoxycholic acid (3a,7p-dihydroxy-5p-cholan-24-oic acid) is present in human bile in small quantities and is of interest because of its therapeutic use as a gallstone-dissolving agent (D8). This bile acid is thought to be... 

Bjorkhem and Einarsson showed that rat liver microsomes in the presence of NADPH are able to convert 7a-hydroxy-4-cholesten-3-one and 7a,12a-dihydroxy-4-cholesten-3-one into the corresponding 3-oxo-5a-steroids (Fig. 11) [168], Liver microsomes from female rats were 3-4 times more active than those from male rats. A similar sex difference was not found in human hver microsomes. The 3-oxo-5a-steroids were efficiently converted into alio bile acids in bile fistula rats. In the presence of both NADPH and NADH, the 3-oxo-5a-steroids were converted into the corresponding 3/3-hydroxy-5a-steroids. As mentioned above, the 3-oxo-5a-steroids are efficiently converted into the corresponding 3a-hydroxy-5a-steroids in the cytosol. 

The quantitative importance of the pathway involving 7a-hydroxy-4-cholesten-3-one and 7a,12a-dihydroxy-4-cholesten-3-one as intermediates in formation of alio bile acids is not known. At least in the rat, the capacity of the microsomal A" -3-oxosteroid 5a-reductase is high, and thus it is surprising that such small amounts of alio bile acids are formed under normal conditions in mammals. It seems probable that this enzyme is inhibited under in vivo conditions. Hoshita et al. found an efficient conversion of 7a,12a-dihydroxy-4-cholesten-3-one into 7a,12a-dihy-droxy-5a-cholestan-3-one in the microsomal fraction of liver from Iguana iguana [170], Alio bile acids are predominant in this species of iguana and it was suggested that the microsomal A -3-oxosteroid 5a-reductase is of major importance for their formation. 

Fig. 11. Sequence of reactions in the conversion of cholesterol into alio bile acids with 7a-hydroxy-4-cholesten-3-one and 7a,12a-dihydroxy-4-cholesten-3-one as intermediates.

Results of various in vivo experiments with labelled bile acid precursors in patients with CTX have been published [185,190,195]. All these experiments show that there is a defect in the oxidation of the steroid side chain in the biosynthesis of cholic acid but are not fully conclusive with respect to the site of defect. Bjorkhem et al. administered a mixture of [ H]7a,26-dihydroxy-4-cholesten-3-one and [ " C]7a-hy-droxy-4-cholesten-3-one to a patient with CTX [195]. The ratio between and C in the cholic acid and the chenodeoxycholic acid isolated was 40 and 60 times higher, respectively, than normal. Similar results were obtained after simultaneous administration of H-labelled 5)3-cholestane-3a,7a,26-triol and 4- C-labelled 5j8-cholestane-3a,7a-diol. The results of these experiments are in consonance with the contention that the basic defect in CTX is the lack of the 26-hydroxylase, but do not per se completely exclude other defects in the oxidation of the side chain. 

Three higher bile acids possessing a keto group were detected in the bile of Alligator mississippiensis, and characterized as 7a,12a-dihydroxy-3-oxo-5)8-cholestan-26-oic acid, 3a,12a-dihydroxy-7-oxo-5/3-cholestan-26-oic acid, and 7a,12a-dihy-droxy-3-oxo-5a-cholestan-26-oic acid [68]. Nothing is known about the formation of these bile acids. 

Although small amounts of the biliary bile acids, 3a,7 ,12a-trihydroxy- and 3a,la-dihydroxy-5)3-cholestan-26-oic acids, were detected, the major fecal bile acids were their 7-deoxy derivatives, 3 ,12 -dihydroxy- and 3a-hydroxy-5 8-cholestan-26-oic acids. Small amounts of 3j8,7a,12a-trihydroxy-5 -cholestan-26-oic acid, 3a,7 -, 3j8,7 -and 3jS,12a-dihydroxy-5)S-cholestan-26-oic acids, and 3 8-hydroxy-5j3-cholestan-26-oic acid were found as well [75]. Since intestinal bacterial in mammals are known to 7a-dehydroxylate C24 bile acids and to interconvert a- and j8-hydroxyl groups (Chapter 12), these C27 bile acids may be products of the intestinal flora in the alligator. 

In 1963, Carey and Haslewood isolated trace amounts of (25/ )-3a,7 ,12a-trihy-droxy-5 8-cholestan-26-oic acid from human fistula bile [96]. The stereochemistry at C-25 of this bile acid was recently confirmed by direct comparison with reference compounds of known absolute configuration [97], This trihydroxy-5j8-cholestanoic acid also occurs in baboon bile [98]. Hanson and Williams found the corresponding dihydroxy bile acid, 3 ,7a-dihydroxy-5 S-cholestan-26-oic acid, in human bile [99]. The occurrence of these higher bile acids, quantitatively of minor importance, is of interest because they are biosynthetic precursors of two primary bile acids of mammalian species, cholic acid and chenodeoxycholic acid, respectively (Chapter 9). 

Eyssen et al. found large quantities of 3 ,7a,12a-trihydroxy-5i8-cholestan-26-oic acid in the duodenal fluid from two unrelated infants with intrahepatic bile duct anomalies [100]. Hanson et al. have confirmed the presence of this bile acid in elevated amounts in bile, serum, urine, and feces from 2 siblings with the same syndrome [101], Considerable amounts of 3a,7a-dihydroxy-5 -cholestan-26-oic acid were found by Parmentier et al. in bile, serum, urine, and feces from 3 other children with the same syndrome [102], Varanic acid was also detected in the bile [102]. In addition, the serum of these patients contained significant amounts of an unusual C,9 bile acid and small amounts of 3a-hydroxy-5 8-cholestan-26-oic acid and 3 -hy-droxycholest-5-en-26-oic acid [102,103]. The structure of the C29 bile acid was shown to be 3a.7a,12a-trihydroxy-27a,27h-dihomo-5]3-cholestane-26,27h-dioic acid (3a,7a,12a-trihydroxy-27-carboxymethyl-5/3-cholestan-26-oic acid) [104]. 

Hanson et al. [105] found increased amounts of 3a,7a,12a-trihydroxy-5 -choIes-tan-26-oic acid, 3a,7a-dihydroxy-5]3-chotestan-26-oic acid, and varanic acid in the urine of 3 infants with Zellweger s syndrome [106]. The same observation was reported by Mathis et al. in 2 other patients with this syndrome [107]. Furthermore, Monnens et al. found an increased amount particularly of the trihydroxy t Uc acid and also of the dihydroxy C27 bite acid in bile and serum from 2 infants with this syndrome [108]. The increased concentrations of higher bile acids may be explained by mitochondrial abnormalities in the liver of patients with Zellweger s syndrome [109]. More recent studies indicate that the occurrence of Q- i acids is related to the absence of peroxisomes in this disease (cf. Chapter 9). 

Dihydroxychol-5-en-24-oic acid has been found as a minor bile acid in human meconium [113] and urine [82], and 7a,12a-dihydroxy-3-oxochol-4-en-24-oic acid in gastric contents from neonates with high intestinal obstruction [110]. 

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