Trihydroxy cholanic acids

Hydroxylation of desoxycholic acid. This perester (1) and desoxycholic acid (2) form a 1 4 molecular complex, which when heated (90°) or irradiated with X>300 nm (25°) decomposes with formation of 3a,50,12o -trihydroxy-cholanic acid (3) and 3-keto-12a-hydroxycholanic acid (4) as the major products. A trace of 3a,12a-dihydroxy-5 -androstane is formed. 

A few other compounds found in bile of specific animal species should be mentioned briefly. Hammarsten (39) isolated a substance from walrus and sea-lion bile that he showed to be a trihydroxy C24 acid. Windaus and Van Schoor (40) showed this to be an a-hydroxy acid, 3,7,23-trihydroxy-cholanic acid. This compound is called jS-phocaecholic acid. Pythocholic acid (C24H40O5) occurs in the bile of the family of snakes that includes boas and pythons (41, 42). The formula 3a,12a,16a-trihydroxycholanic acid has been suggested (43). Ursodeoxycholic acid (44) occurs in bear bile and is apparently 3a,7 -dihydroxycholanic acid. Hyodeoxycholic acid (3a,6a-dihydroxycholanic acid) has been isolated from hog bile. 

Pythocholic acid has been isolated from several species of snakes of the family Boidae (132). It was characterized as a 3-, 12-, 15- or 16-trihydroxy-cholanic acid by Haslewood and Wootton (132) and Haslewood (133). The assignment of the 16a-hydroxyl group is consistent with optical rotation data (134). The acid takes its name from the python where it is the principal bile acid. Despite its character as a unique trihydroxycholanic acid, pythocholic acid is probably not a primary acid, but rather formed by hydroxylation of deoxycholic acid returning from the gut (135). 

In relation to the pathway of metabolism of cholesterol to the 12-deoxy bile acids as proposed by Mitropoulos and Myant (132), the metabolism of the antiatherogenic cholestane-3/3,5a,6 -triol-4- C in the rat is of particular interest. Most of the fecal or biliary radioactivity was associated with the bile acid fraction. The major biliary metabolite was identified as 3/3,5a, 6 -trihydroxy-cholanic acid (137). 

The most important end products in mammalian cholesterol metabolism are the bile acids. The parent C24-acid is cholanic acid with a ring structure identical to that of coprostanol (A/B cis). The bile acids are hydroxylated cholanic acids, all hydroxyl-groups have a-orientation. Consequently, they do not form digi-tonides. The principal acids are cholic acid (3a, 7a, 12a-trihydroxy-cholanic acid), chenodeoxycholic acid (3a, 7a-dihydroxycholanic acid) and deoxy-cholic acid (3a, 12a-dihydroxycholanic acid). Lithocholic acid (3a-hydroxycholanic acid) also occurs in human bile, but only in small amounts. 

The cmc of bile salts is strongly influenced by its structure the trihydroxy cholanic acids have a higher cmc than the less hydrophilic dihydroxy derivatives. As expected, the pH of solutions of these carboxylic acid salts has an influence on micelle formation. At sufficiently low pH, bile acids which are sparingly soluble will be precipitated from solution, initially being incorporated or solubilized in the existing micelles. The pH at which precipitation occurs, on saturation of the micellar system, is generally about one pH unit higher than the pK of the bile acid. 

Cholic add is a trihydroxy cholanic acid in which the hydroxyl groups occupy positions 3, 7 and 12 in the nucleus. 

Cholanic acid C24H40O2, a monobasic saturated acid containing four hydroaromatic rings, is the parent substance of the two natural acids, which are its trihydroxy- and dihydroxy-derivatives. It is very highly probable that the following structural formula for cholic acid is correct ... 

Bile acids have historically received much less attention than other steroids, for example the corticosteroids however, now that useful thertqreutic effects ate being observed from some bile acids, there is fresh interest in Ais area. A strain of Cunninghamella Uakesleeana has been isolated that will 15p-hy-droxylate lithocholic acid (80 equation 26) in 31% yield.Further reaction is possible to give 3a,lip,15p-trihydroxy-5p-cholanic acid (15%), 3a,15p,18a-trihydioxy-5p-cholanic acid (4%) and 3a,lla,15p-trihydroxycholanic acid (9%). Taurolithocholic acid (81 equation 27) can be 7p-hydroxy-lated in virtually quantitative yield by Mortierella ramanniana. ... 

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. 

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).

The conversion of lithocholate to 3a,6/8-dihydroxy-5/8-cholanate by the rat [84-86], mouse [87] and chicken [88] confirmed the presence of an active hepatic 6)8-hydrox-ylase. Earlier studies reported the metabolism of chenodeoxycholate [89,90] in the rat and mouse [81,91,92] to a-murocholic acid (3a,6)8,7a-trihydroxy-5)8-cholanic acid) and to )8-muricholic acid [89,90,93,94] (3a,6)8,7)8-trihydroxy-5)8-cholanic acid). 

Other precursors of the muricholates via 6)8-hydroxylation include 5)8-cholanic acid [78], lithocholic acid [84-86], 7-oxolithocholic acid [95,96], and ursodeoxycholic acid (3a,7j6-dihydroxy-5/3-cholanic acid) [97], The rat metabolized 12a-hydroxy-5/S-cholanic acid to 6/S,12a-dihydroxy-5)S-cholanic acid [83] and a small amount of 6)3,7a,12a-trihydroxy-5 -cholanic acid [98]. 3a,6)8,12a-Trihydroxy-5)8-cholanic acid was isolated from urine of surgically jaundiced rats after administration of de-oxycholate [99]. A series of bile acids from rat bile of unconfirmed structures but containing the 6/3,7/3-diol will be reviewed in Section II1.3. 

The boa constrictor and python (species Boidae) are unique in that the major bile acid is pythocholic acid (3a,12a,16a-trihydroxy-5/8-cholanic acid) along with varying... 

As noted earlier, bile acids were among the first steroids to be obtained in pure crystalline form. These compounds played an important role in the effort devoted to divining the structure of steroids. Bile acids as a result acquired a sizeable number of trivial names, most of which gave little information as to their chemical structure. One approach to systematic names is based on the hypothetical cholanoic acid 8-1 (Scheme 8). Bile acids are then named as derivatives of this structure using the mles used for other classes of steroids. Note the cis A-B ring fusion in this series. The systematic name for 8-2, lithocholic acid, is then simply 3a-hydroxy-5/3-cholanic acid. Chenodeoxycholic acid, 8-3, becomes 3a,7a-dihydroxy-5/3-cholanic acid. The predominant acid in bile, 8-3, is cholic acid itself, or, 3a,7a,12a-trihydroxy-5 )8-cholanic acid. 

Reaction of steroidal tosylates with KNO2 in DMSO or DMF gave reasonable yields of alcohols with inverted configuration. The previously reported epi-merization at C-3 during Raney nickel-catalysed hydrogenation of methyl 3, 1 a-dihydroxy-12-oxo-5/8-cholanate was incorporated in a report of the synthesis of 3/3,7a,12j8-trihydroxy-5/3-cholanic acid and the 3a,7a,12/3-trihydroxy-analogue. Conversion of mestranol into epimestranol was achieved by treatment of the 17-mesylate with silver nitrate in aqueous THF. ... 

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