Allocholic acid

FI GURE 4.3 Structures of allocholic acid (petromyzonol sulfate is identical apart from replacement of the carboxyl group with sulfate), taurine-conjugated bile acid, and geosmin. 

Yun, S-S., Scott, A. P., and Li, W. (2003). Pheromones of the male sea lamprey, Petromyzon marinusL. structural studies on a new compound, 3-keto allocholic acid, and 3-keto petromyzonol sulfate. Steroids 68,297-304. 

Bile alcohols and Allocholic acid trans alp trans Pla trans Pla... 

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. 

Fig. 10. Sequence of reactions in the conversion of cholestanol into allocholic acid.

Noma et al. found 2 keto bile alcohols in unconjugated form in bullfrog bile [42]. Their structures were determined as 24-dehydro-26-deoxy-5a-ranol and its 5 isomer by comparison with synthetic 3a,7a,12a-trihydroxy-27-nor-5a- and 5/8-choles-tan-24-ones, prepared from allocholic acid and chohc acid, respectively [41]. 

Fig. 1. Comparison of structures of 5a- and 5/8-bile acids. Allocholic acid (3a,7a,12a-trihydroxy-5a-cholanic acid) cholic acid (3a,7a,12a-trihydroxy-5 -cholanic acid).

In the 5a series allochenodeoxycholate is 12a-hydroxylated to allocholate in the bile fistula rat [131] or with a hepatic microsomal preparation from rat, rabbit or human liver fortified with NADPH [152,153]. Kallner [133] noted that small amounts of more polar derivatives were present in rat bile, with largely unchanged allochenodeoxycholate. AUohyocholate was identified as a minor metabolite [154]. With rabbit liver microsomal preparations, allochenodeoxycholate is a competitive inhibitor for 12a-hydroxylation of 7a-hydroxy-cholest-4-en-3-one and 5a-choles-tane-3a,7a-diol, precursor of cholic and allocholic acids, respectively [155]. Allo-cholic acid has also been characterized as a metabolite of 3 8,7a-dihydroxy-5-cholenic acid after intraperitoneal injection into carp [156]. 

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]. 

Petromyzonol sulfate and allocholic acid are commonly produced and released by larval petromyzontid lampreys and likely used as part of a common evolution-arily conserved pheromone. This scenario is reasonable because different lamprey species have similar larval (silt) and spawning (gravel) habitat requirements, and their larvae derive no apparent benefit from producing compounds that serve as an attractant for adults (Fine et al. 2004). However, not all of the activity of the larval pheromone could be explained by these two bile acids released by larvae (Vrieze and Sorensen 2001). A recent study identified two new compounds, petromyzona-mine disulfate and petromyzosterol disulfate, released by larval sea lampreys and hypothesized to function as pheromones (Sorensen et al. 2005). Currently, there is no evidence that crustaceans use long distance pheromones. 

A method for the preparation of allochenodeoxycholic and allocholic acids from the corresponding cholic acids has been reported. The key step in the synthesis is the oxidation-dehydrogenation of 3a-hydroxy-5p-bile acid formyl esters 816 to give oxodienes 817 (Scheme 3.322) [1115]. 

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,... 

Fig. 6. Conversion of cholesterol into allocholanoic acids. I, Cholesterol II, 5-cholestene-3/5,7a-diol III, 7a-hydroxy-4-cholesten-3-one XXIV, cholestanol XXV, 5a-choles-tane-3i ,7a-diol XXVI, 7a hydroxy-5a-cholestan-3-one XXVII, 5a-cholestane-3a,7a-diol XXVIII, 5a-cholestane-3a,7a,12a-triol XXIX, allochenodeoxycholic acid XXX, allocholic acid.

Bile salts with a steroid structure appear to be confined to vertebrates (76). In some evolutionarily more primitive vertebrates, the major bile salts are sulfate esters of polyhydroxy C27- and C26-steroids and/or taurine-conjugated C27-steroid acids. In other primitive vertebrates, C24 bile acids, usually cholic acid and/or allocholic acid, or mixtures of primitive bile salts (bile alcohols and C27 bile acids) and modern bile salts (C24 bile acids) occur. Most of the work concerning the structure and occurrence of primitive bile salts has been carried out in the laboratories of G. A. D. Haslewood and T. Kazuno, and Haslewood and collaborators have accumu-... 

Section IV Mui and Elliott (197) have shown that allochenodeoxycholic acid is converted to a small extent into allocholic acid in the rat. 

Alchornoic acid, in E-00014 Aldehyde MNA, see M-00125 Alcpric acid, see C-00039 Alcprolic acid, see C-00036 Aleprylic acid, see C-00038 Alcuritic acid, m T-00191 Alexandrin, in S-00008 Allocholic acid, in T-00188 Ambrettolic acid, see H-00282 Ambrettolic acid lactone, see H-00201 Ambrettolide, in H-00201 /rfl/w-Ambrcttolidc, in H-00201... 

Figure 13 Chromatograms of gall bladder extracts from the pacific lamprey (A), western brook lamprey (B), and sea lamprey (C). Petromyzonol sulfate (PZS) and allocholic acid (ACA) cleanly separate from each other and hyocholic acid (HA) and lithocholic acid (LCA) are the internal standards. (Reprinted with permission from Steroids, 68 (2003) 515-523 Elsevier.)...

Until recent years, bile salts were considered to be exclusively 5 8 steroids. The first recognition of the occurrence of 5a or alio bile salts came from the studies of Anderson and Haslewood (165) who synthetized allocholic acid and identified it as a previously unidentified naturally occurring acid from fish bile. The earliest isolation of allocholic acid appears to have been that by Ohta from the bile of the Gigi fish (166). Since that time allocholic acid has been isolated from the bile of a large number of fishes, birds, and, to a smaller extent, mammals (4). It has also been detected in human feces (121). Allocholic acid may be prepared from cholic acid by allomerization of the 6,7-ketol in hot alkali (165) or by treatment of the 3-keto acid with Raney nickel in boiling isopropyl benzene (167). 

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). 

Bile salts from larval lampreys have yielded a C24 alcohol characterized by comparison with the product obtained by LiAlH4 reduction of the ester of allocholic acid (196). Petromyzonol is the only 34 alcohol thus far identified as a natural product. 

Allochenodeoxycholic acid has been shown to be a biliary constituent of the giant salamander (39) and a metabolite of cholestanol (40) and of allolithocholic acid in the bile fistula rat (41). Haslewood (25) has reasoned that a search for allochenodeoxycholic acid in the bile of the germ-free chick might be successful, since allocholic acid is present in bile of these animals and chenodeoxycholic acid is the major bile acid in this species however, he has not been able to establish its occurrence. 

A probable intermediate in the biosynthesis of allocholic acid, 3a,7a, 12a trihydroxy-5a-cholestan-26-oic acid, has been found in the bile of the giant salamander (39). Amimoto (43) obtained allocholic acid and a second radioactive acidic metabolite from bile of the giant salamander after administration of 27-deoxy-5a-cyprinol (3a,7a, 2a, 26-tetrahydroxy-5a-cholestane). The unknown acid was esterified, reduced with LiAlH4, and the product identified as 27-deoxy-5a-cyprinol. Okuda et at. (44) isolated a few crystals (m.p. 227 °C) from the bile of iguana and obtained the same product on reduction of the ester with LiAlH4. 

On the other hand, methyl allocholate and methyl cholate are not separated by crystallization (19, 19a, 47). Karavolas et al. (28) achieved a separation of 91 % of allocholic acid from cholic acid by repeated crystallization from benzene, acetone, aqueous methanol, and benzene-acetone. Final separation was effected by chromatography on Florisil. 

Haslewood (25) has discussed the value of infrared spectroscopy for the characterization of bile acids and has indicated that bands at about 9.3, 9.6, 10.2, 10.5, and 10.95 p are especially useful for detection of the cholic acid nucleus. Earlier he and Anderson (69) noted the importance of absorption bands at 10.4 and W.2 p for the identification of allocholic acid. He has pointed out the prominence of bands at about 9.2, 9.7, 9.9, 10.4, and 11.2 /i in the spectrum of allocholic acid. Those bands between 9.0 and 10.0 p due to the C-0 stretching frequency can be attributed to the axial hydroxyl groups at Cj, C, and Cjj. This is apparent from the data in Table IV which show the absorption bands for a series of substituted allo-acids in the vicinity of the bands reported for allocholic acid. The band found in the vicinity of 9.9 p can be attributed to the 3a-hydroxyl group replacement with a 3/9-hydroxyl group produces a hypsochromic shift. 

Diaitonin has been used to precipitate the 3 5-epimer of allocholic acid... 

The initial studies of Anderson and Haslewood on the identification of Ohta s acid (79) sparked efforts to synthesize allocholic acid. Early attempts to reduce catalytically methyl 3a,12a-diaceto. y-7-ketochol-5-enoate to the... 

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