Allochenodeoxycholic acid

Like its 5p-isomer this acid undergoes 7a-hydroxylation in the liver to provide allochenodeoxycholic acid (41). Several other metabolites have not been characterized. Following intracecal administration lithocholic, allochenodeoxycholic and its 5 -isomer have been identified in bile. 

In contrast to its 5,3-isomer this dihydroxy acid is not metabolized extensively after intraperitoneal administration (41, 171). From experiments with cholestanol- C in the hyperthyroid rat (122) proportionately more /3-muricholate was found in bile than in the normal rat, but less than 2% of the chromatographed biliary C was found in these fractions, suggesting that the 5a-cholestane (or 5a-cholane) nucleus was not metabolized in rat liver as extensively as the 5/3 ring system (40). Kallner (41) suggested that the minor unidentified metabolites derived from allochenodeoxycholic acid are related to the muricholic acids derived in the rat from chenodeoxycholic and lithocholic acids (138, 139, 140). Less than 5% of the chromatographed C is present in these fractions the major metabolite is allocholic acid and a minor constituent may be allohyocholic acid (171). 

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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. 

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.

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

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. 

Allolithocholic acid has been shown recently to be a metabolic product of allochenodeoxycholic acid in the rat after intracecal administration (41). 

In a recent report Nakada et al. (89) detailed the preparation of 3,7-dioxo-5a-cholanoic acid (m.p. 185-187 °C) from 3 -hydroxy-7-keto-chol-5-enoic acid obtained from oxidation of 3/3-hydroxy-chol-5-enoic acid with CrOg and subsequent reduction. Reduction of this material should provide the 3jS-epimer of allochenodeoxycholic acid and its 7p-epimer. 

Administration of 5a-cholestan-3 3,7a-diol-4- C-3a- H to rats with bile fistulas has confirmed the conversion of this diol (XXXII) to allocholic, and allochenodeoxycholic acids and their 3/3-isomers (126). The ratio of di- to trihydroxy allo-acids derived from the above diol was similar to that obtained fromcholestanol(28). Since the ratio of H to of the 3,5-hydroxy allo-acids was the same as the administered diol, a 3-keto intermediate is not an obligatory prerequisite for oxidation of the side chain. 

Recent investigations (131) have shown the in vivo conversion of tritiated samples of 5a-cholestane-3,26,-diol (XXXIX) and 5a-cholestane-3y3,7a,26-triol (XL) to allocholic and allochenodeoxycholic acids and their 3 -isomers in the bile fistula rat. Small amounts of allolithocholic acid and its 3 -isomer were also detected from the above diol. A summary of the current status of knowledge in these metabolic transformations is given in Fig. 12. 

Bile Acids and Sterols. XCIV. Synthesis of Allochenodeoxycholic Acid J. Biochem. (Tokyo) 61(6) 750-755 (1967) CA 68 3104b... 

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