Allodeoxycholic acid

In the rat this acid is converted to allocholic acid (55) in the intestine it is regenerated from allocholic acid (41, 123). After intracecal administration 34% of the biliary dihydroxy acid and 47% of the fecal dihydroxy acid is deoxycholic acid (45). 

Like cholic acid this allo-acid is not metabolized by the rat on passage through the liver in the intestine it is converted to cholate, allodeoxycholate, and deoxycholate (41, 123). 

After intraperitoneal administration to the rat, 90% of this acid is recovered unchanged in bile (141) 0.6% was present in monohydroxy acids of which 60% was identified as 3/3-hydroxy allocholanoic acid. About 9% was converted to unidentified trihydroxy acids. In vitro experiments with liver homogenates indicate less extensive metabolism of this dihydroxy allo-acid in this case allolithocholate appears to be formed instead of the 3j9-isomer. 

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Deoxycholic acid can be converted into allodeoxycholic acid in rabbits and rats [159,160], Kallner has shown that this conversion probably occurs by intermediate formation of the corresponding 3-oxo-5/8-, S-oxo-A - and 3-oxo-5a-bile acids [161,162]. Most or all of these reactions are catalysed by intestinal microorganisms. The reactions are reversible and it has been shown that allocholic, allo-chenodeoxycholic, allodeoxycholic and allolithocholic acid can be converted into the corresponding 5j8-bile acids. 

Hofmann and Mosbach (1964) have used chromatography, infrared spectroscopy, and optical rotatory dispersion to identify allodeoxycholic acid as the major component of gallstones induced in the rabbit by 5a-cholestan-3) -ol. 

TThe following systematic names are given to steroids and bile acids referred to by trivial names cholestanol, 5a-cholestan-3/5-ol cholic acid, 3a,7a,12a-trihydroxy-5j3-cholanoic acid hyocholic acid, 3a,6a,7a-trihydroxy-5/S-cholanoic acid a-muricholic acid, 3a,6/S,7a-trihydroxy-5/S-cholanoic acid /5-muricholic acid, 3a,6/S,7/S-trihydroxy-5/S-cholanoic acid allocholic acid, 3a,7a,12a-trihydroxy-5a-cholanoic acid chenodeoxycholic acid, 3a,7a-dihydroxy-5/5-cholanoic acid deoxycholic acid, 3a,12a-dihydroxy-5iS-cholanoic acid allochenodeoxycholic acid, 3a,7a-dihydroxy-5a-cholanoic acid allodeoxycholic acid, 3a,12a-dihydroxy-5a-cholanoic acid lithocholic acid, 3a-hydroxy-5/5-cholanoic acid. 

Allocholanoic acids (5a-cholanoic acids) are found mainly in lower animals (68,76), but small amounts of allocholic acid (3a,7a,12a-trihydroxy-5a-cholanoic acid), allodeoxycholic acid (3a,12a-dihydroxy-5a-cholanoic acid), and probably also allochenodeoxycholic acid (3a,7a-dihydroxy-5a-cholanoic acid) may be present in bile and feces of mammals (68,76,102). Karavolas et al. (Ill) and Ziller et al. (112) have shown that cholestanol is converted into allocholic acid and allochenodeoxycholic acid in rats with a biliary fistula. The conversion of cholestanol into allocholic acid has also been shown in the rabbit (113). Allodeoxycholic acid is a secondary bile acid, formed from allocholic acid (113,114) and deoxycholic acid (115,116). The early steps in the sequence of reactions from cholestanol to allocholic acid (Fig. 6) have been the subject of two recent investigations. Shefer et al. (17) have shown that the microsomal fraction of rat liver homogenate fortified with NADPH catalyzes 7a-hydroxylation of cholestanol. Bjorkhem and Gustafsson (117) have compared the rates of 7a-hydroxylation of cholestanol,... 

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 natural occurrence of the 5a-epimer of deoxycholic acid was first demonstrated by Danielsson, Kallner, and Sjovall (62). The original isolation of this compound was probably by Kishi (61) who named the unidentified acid lagodeoxycholic acid from rabbit bile. In addition to its occurrence in rabbit bile, allodeoxycholic acid is present in rabbit feces (62) and accumulates as the glycine conjugate in gallstones of rabbits fed cholestanol (168). Allodeoxycholic acid may be synthesized from cholic acid by reactions similar to the preparation of allocholic acid (62,168). 

The trans fusion of rings A and B in the allo-acids produces a more planar molecule than the 5 3 acid and contributes to the poorer detergency of glyco allodeoxycholate and consequent poorer solubility of the calcium salt (36). The Krafft point (critical micellar temperature) of several allo-acids has been determined and discussed (64). In contrast to the notorious character of deoxycholic acid to complex with a large variety of other substances, no evidence has been reported for the formation of choleic acids by allodeoxycholic acid. 

Hofmann and Mosbach (36) have identified allodeoxycholic acid as the conjugate with glycine in gallstones from rabbits fed a diet of 1 % cholestanol. Subsequent experiments have confirmed the origin of allodeoxycholic acid in this species from allocholic acid by intestinal dehydroxylation at (123) the intestinal anaerobe capable of this reaction in the rabbit has been characterized (38). 

Sulfated alio bile acids occur more abundantly or exclusively in bile of female rats compared to male rats [63]. Allochenodeoxycholate monosulfate was the major sulfated alio acid from the female none was detected in bile of the male. Other monosulfates identified include allocholate, and the 3 epimers of allochenodeoxycholate and allocholate. From female rat bile collected 48-60 h after cannulation allochenodeoxycholate constituted about 63% of the mono- and disulfate fractions none was found in bile from male rats. Sulfates of allocholate and the 3j8 epimers of allochenodeoxycholate and allocholate were present in smaller amounts. Initial collections of bile (0-12 h) contained allodeoxycholate and its 3j8 epimer in the monosulfate fraction. 

Similarly, after intracecal administration of allocholic acid to rats, bile contained allocholate, cholate, allodeoxycholate and deoxycholate from allochenodeoxycho-late, chenodeoxycholate and allochenodeoxycholate were the products, and from allolithocholate mainly allochenodeoxycholate and chenodeoxycholate were obtained [133]. 

Partial separations of the substituted methyl allocholanoates have now been achieved by crystallization. Kallner (41, 45) has reported the removal of 82% of the radioactivity after three crystallizations of a mixture of methyl allolithocholate- H and methyl lithocholate 90% of the tritium was removed by several crystallizations of a mixture of methyl lithocholate- H and allolithocholate. Similarly, more than 90% of the radioactivity was removed from a mixture of methyl deoxycholate- H and allodeoxycholate after three crystallizations from aqueous acetic acid or aqueous methanol. Methyl 3/3,12a-dihydroxy-5 -cholanate was separated from methyl deoxy-cholate by crystallization from aqueous methanol. Thomas et al. (46) reported the separation of 3a,6/3-dihydroxy-5 - or 3a,6a-dihydroxy-5 -cholanoic acid from 3a,6/3-dihydroxy-5 -cholanoic acid by crystallization from aqueous acetone or a mixture of methanol, ether, and hexane. 

The specific rotations of the acid and methyl ester are given in Table I with the solvent and concentration molecular rotations have been calculated for the methyl esters where specific rotations are available. Agreement between the calculated and found values is reasonably good for most substances. Although allolithocholic, allochenodeoxycholic, allodeoxycholic, and allo-cholic acids are less dextrorotatory than their corresponding 5 acids (65), the specific rotations of a number of the other allo-acids are either equivalent to or more dextrorotatory than the comparable 5 -epimer, thus precluding a general conclusion for this class of compounds. Optical rotatory dispersions of a few 3-keto-allo derivatives have been reported (34, 66, 67, 68, 40). 

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