Cholic acid, from cholesterol

The synthesis of cholic acid from cholesterol in rodents proceeds via 7a-OH-cholesterol, leading to a trihydroxy derivative which finally loses a side chain, resulting in the formation of cholic acid (1). The synthesis appears to proceed similarly in the human liver (12). Trihydroxycoprostanic acid, which is a precursor of cholic acid and which is formed from cholesterol... 

Early in vitro studies showed that mitochondria from livers of hyperthyroid rats did not oxidize cholesterol-26- C to C02 at a faster rate than similar preparations from normal animals (12). A more recent study (13) led to the conclusion that the effects of thyroid hormones on bile acid metabolism must take place at a biosynthetic step preceding side-chain oxidation, perhaps involving hydroxylation of the steroid nucleus. However, it must be realized that the normal substrate for side-chain oxidation leading to the formation of cholic acid from cholesterol is not cholesterol itself but presumably 3a,7afl2a-trihydroxy-5/5-cholestane (14,15), and the substrate for the side-chain oxidation leading to chenodeoxycholate is, presumably, 3a,7a-dihydroxy-5/5-cholestane (16). Thus results of in vitro experiments in which cholesterol is employed as the substrate must be interpreted with caution, since mitochondria do not have the enzyme system required for formation of the triol and diol from cholesterol. 

Bergstrom S, Lindstredt S, Samuelson B, Corey EJ, Gregoriou GA (1958) The stereochemistry of 7a-hydroxylation in the biosynthesis of cholic acid from cholesterol. J Am Chem Soc 80 2337-2338... 

Part of the cholesterol newly synthesized in the liver is excreted into bile in a free non-esterified state (in constant, amount). Cholesteiol in bile is normally complexed with bile salts to form soluble cholic acids, Free cholesterol is not readily soluble and with bile stasis or decreased bile salt concentration may precipitate as gallstones. Most common gallstones are built of alternating layers of cholesterol and calcium bilirubin and consist mainly (80-90%) of cholesterol. Normally. 80% of hepatic cholesterol arising from blood or lymph is metabolized to cholic acids and is eventually excreted into the bile in the form of bile salts. 

Bile alcohols are polyhydroxy C27 sterols that serve as intermediates in the biosjmthesis of cholic acid and chenodeoxycholic acid from cholesterol (1, 2). Recently several studies have shown that increased amounts of bile alcohols namely 27-nor-5p-cholestane-3a,7a,12a,24, 25-pentol and 5P-cholestane-3a, 7a,12a,25,26-pentol are excreted (as glucuronides in urine of patients with liver diseases such as primary biliary cirrhosis (3), liver cirrhosis (4, 5) and a-antitrypsin deficiency (6). Ichimiya et. al., described the occurrence of 5P-cholestane-3a,7a,12a,26,27-pentol (5P-cyprinol) and 5P-cholestane-3a,7a,... 

The formation of the other major primary bile acid, chenodeoxycholic acid, from cholesterol is similar to that of cholic acid, except that no 12-hydroxylation takes place. 

Little further was substantiated about cholic acid (or about bile acids generally) for nearly five decades. The name, cholic acid, had become well established, but trivial names based partly on imperfect characterization were common, so that consideration of nomenclature was a part of Wieland s first report on the bile acids in 1912 (56). A review of the evidence then available included that cholic acid was a trihydroxy, monocarboxylic acid and that two of the alcohols were secondary. The final presentation of the structure of cholic acid awaited the correct steroid formulation in 1932 (113, 114). By that time the structural relationship between the sterols and bile acids was well established. The preparation of cholanic acid from cholic acid had been reported in the paper by Wieland and Weil in 1912 (56). The preparation of cholanic acid from cholesterol (through coprostane) was reported in 1919 by Windaus and Neukirchen (55). 

Fig. 32.1. The classical ( neutral ) pathway for the synthesis of bile acids from cholesterol, where the modification of the steroid nucleus occurs prior to side-chain modification. Also illustrated are the inborn errors of bile acid synthesis and the resulting abnormal metabolites. 32.1, 3) -hydroxy-A -C27-steroid dehydrogenase (3) -HSDH) deficiency 32.2, A -3-oxosteroid 5 -reductase deficiency 32.3, sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis, CTX) PD, peroxisomal disorders (defects of peroxisome biogenesis and peroxisomal j -oxidation). The abnormal metabolites that are readily detected by analysis of urine by LSI-MS are shown in boxes. Cholic acid can also be synthesised from 5 -cholestane-3a,7a,12a,25-tetrol this is the so-called microsomal or 25-hydroxylase pathway of cholic acid synthesis, which provides an alternative route for side-chain modification other than peroxisomal j -oxidation...

That cholic acid originates from blood cholesterol has been demonstrated by feeding cholesterol-D to a dog with a bile-renal fistula followed by the isolation of cholic-D acid from the urine. Comparison of the isotope content of serum cholesterol with cholic acid showed that at least 87 % of the cholic acid was produced from cholesterol. Apparently the reverse conversion, transformation of cholic acid to cholesterol, does not take place. When rabbit liver was perfused with blood containing 7-dehydrocholesterol, desoxycholic acid was isolated from the perfusate. It is of interest to note that scymnol (XXII), a substance very closely related to cholesterol (I) on the one hand and to cholic acid (XVIII) on... 

Lifschiitz, 1914). This relationship was show ii conclusively by Bloch et al. (1943), who gave deuterium-labolcd cholesterol to a dog with cholecysto-nephrostomy and isolated labeled cholic acid from the urine. 

As we have seen in this chapter steroids have a number of functions in human physiology Cholesterol is a component part of cell mem branes and is found in large amounts in the brain Derivatives of cholic acid assist the digestion of fats in the small intestine Cortisone and its derivatives are involved in maintaining the electrolyte balance in body fluids The sex hormones responsible for mascu line and feminine characteristics as well as numerous aspects of pregnancy from conception to birth are steroids... 

FIGURE 25.41 Cholic acid, a bile salt, is synthesized from cholesterol via 7o -hydroxy-cholesterol. Conjugation with taurine or glycine produces taurocholic acid and glycocholic acid, respectively. Taurocholate and glycocholate are freely water-soluble and are highly effective detergents. 

The primary bile acids are synthesized in the liver from cholesterol. These are cholic acid (found in the largest amount) and chenodeoxycholic acid (Figure 26-7). 

Fig. 5.4.4a Methyl ester-trimethylsilyl (TMS) ethers of BAs from a plasma sample, b n-Butyl ester-TMS ethers of BAs from a plasma sample (adapted from [15]). 1 Nor-cholic acid, 2 litho-cholic acid, 3 deoxycholic acid, 4 chenodeoxycholic acid, 5 cholic acid, 6 ursodeoxycholic acid, a cholesterol, b sitosterol)...

The C>4 bile acids arise from cholesterol in the liver after saturation of the steroid nucleus and reduction in length of the side chain to a 5-carbon add they may differ in the number of hydroxyl groups on the sterol nucleus. The four acids isolated from human bile include cholic acid (3,7,12-tiihydroxy), as shown in Fig. 1 deoxycholic acid (2,12-dihydroxy) chenodeoxycholic acid (3,7-dihydroxy) and lithocholic acid (3-hydroxy). The bile acids are not excreted into the bile as such, but are conjugated through the C24 carboxylic add with glycine or... 

Some dietary factors can also change the bile acid species and, by doing so, alter cholesterol absorption. The liver synthesizes the primary bile acids, cholic and chenodeoxycholic acid. Bacteria in the intestine can convert some of the primary bile acids into secondary bile acids, producing deoxycholic from cholic acid and lithocholic from chenodeoxycholic acid. When certain dietary components alter the intestinal microflora, the rate of secondary bile... 

It is well known that bile acids are produced in the liver of vertebrates for digestion and absorption of fats and fat-soluble vitamins. Starting from isoprene, a series of biochemical reactions yield a key compound, cholesterol, which is converted to primary bile acids, such as cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) and lithocholic acid (LCA). Hereafter the abbreviations of bile acid derivatives can be seen by consulting Table 1 and Figure 1. 

Our study on the distribution of electron transferring proteins in animal sources is still in progress. From present knowledge, adrenodoxin can be found in adrenal cortexes from pig, beef, and rat. Further, a similar protein was isolated from pig testis (see II-A-2), and it was also found in the ovary. However, brain, heart, liver, kidney, and pancreas appear to lack adrenodoxin-like protein. If this is correct, the proteins of the ferredoxin family are located solely in the glands which directly act in the biosynthesis of steroid hormones. It is of interest that adrenodoxin-like protein does not participate in the steroid hydroxylation involved in cholesterol and cholic acid biosyntheses. All of these reactions without the participation of adrenodoxin are similar to enzymes responsible for microsomal non-specific hydroxylation, which consist of the following sequence of electron transfer ... 

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