Hyodeoxycholic acid formation

Mosbach and Bevans (134) showed that cholestanol-induced cholecystitis and cholelithiasis could be inhibited by the simultaneous administration of dehydrocholic acid and that the extent of inhibition depended on the relative concentrations of the two steroids. Similar observations were made by Ricci et al, (135). Deoxycholic and cholic acids were also effective inhibitors (136), but hyodeoxycholic acid did not suppress gallstone formation and appeared to increase biliary tract inffammation. Several non-bile acid choleretics were without inhibitory effects (136). Lindelof and van der Linden (32) found that intravenous injections of cholecystokinin every 8 hr did not suppress and may actually have enhanced gallstone formation. The inhibition of cholelithiasis by dehydrocholic, deoxycholic, and cholic acids was not accompanied by a decrease in cholestanol absorption but did result in increased tissue cholestanol levels, suggesting a decrease in the conversion of this sterol to bile acids (134,136). Conversely, methyl testosterone apparently inhibited stone formation by interfering with cholestanol absorption, since tissue and serum levels of cholestanol were reduced (137). Olive oil has been shown to facilitate stone formation (138), perhaps by enhancing cholestanol absorption (137). 

The occurrence of a species-specific bile acid in pig bile [Haslewood (1) Haslewood and Sjovall (2)] and of two such acids in rat bile [Bergstrom and Sjovall (3) Hsia et al. (4) Matschiner et al. (5)] was observed almost simultaneously. After their isolation and characterization, these acids were found to be isomeric 3a,6,7-trihydroxy-5/5-cholanic acids. The acid from pig bile was named hyocholic acid [Haslewood (6) Ziegler (7)], and the two acids from rat bile were named a- and /3-muricholic acids [Hsia et al. (8)]. The fourth isomer of these glycols was identified as a metabolite of hyodeoxycholic acid (3rt,6a-dihydroxy-5 9-cholanic acid) in the rat [Matschiner et al. (9, 10)], and was named ry-muricholic acid [Hsia et al. (8)]. The vicinal glycol structures in ring B of these acids are unique features, but even more unique are their species-specific characteristics which are particularly demonstrated in the metabolic pathways that lead to their formation. 

A study by Einarsson (26) has confirmed an earlier observation of Lin et al. (27), and has established that hyodeoxycholic acid is formed in the intact rat. It has been suggested that the formation of hyodeoxycholic acid is a result of the interplay of metabolic activities of the liver and intestinal microorganisms [Einarsson (26) Okishio and Nair (28)]. Although isolation of o>-muricholic acid from normal rat bile has never been attempted, it is likely to be present in normal rat bile since it is a metabolite of hyodeoxycholic acid. 

Confirmative evidence of the proposed structure was obtained from partial synthesis of hyocholic acid [Hsia et al. (30)]. An important intermediate in the synthesis was 3a,6a-dihydroxy-7-keto-5 -cholanic acid (VII, Fig. 2), first prepared by Takeda et al. (35). The 3 - and 6a-hydroxyl groups in VII were established by the formation of hyodeoxycholic acid (IX) after hydrogenolysis of the ethylenedithioketal derivative (VIII) with Raney nickel. Hyocholic acid was obtained from VII either by reduction with sodium borohydride or by hydrogenation in the presence of platinum both methods were known to produce the axially oriented 7a-hydroxy from 7-keto bile acids [Mosbach et al. (36) Iwasaki (37)]. More direct evidence for the la-hydroxyl group in hyocholic acid was found in a later study [Hsia et al. (8)], when hyocholic acid was derived from bromohydrin acetate XII (Fig. 3),... 

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