Cholic acid synthesis

More frequently encountered are acquired defects in bUe acid synthesis, which have been noted in Liver diseases such as hepatitis and cirrhosis. In acute hepatitis, alterations of bile acid synthesis and conjugation occur because of hepatic parenchymal cell disease. In cirrhosis, there is a marked reduction in cholic acid synthesis with a low concentration of biliary deoxycholic acid. These abnormalities are due both to decreased synthesis and to portosystemic shunting. The... 

Fic. 3. Metabolic steps in the conversion of diolesterol (I) to the intermediate in cholic acid synthesis, 5P-cholestane-3a,7a,I2o-triol (V), or the corresponding intermediate in che-nodeoxycholic acid synthesis, 5p-cho)estane-3a,7a-dioI (VI). 

P14. Poulos, A., and Whiting, M. J., Identification of3a,7a, 12a-trihydroxy-5 -cholestan-26-oic aod, an intermediate in cholic acid synthesis, in the plasma of patients with in ntile Return s disease. J. Inherited Metab. Dis. 8, 13-17 (1985). 

Patients with hypercholesterolemia do not appear to have significant alterations in bile salt synthesis rates, but patients with combined hypercholesterolemia and hypertriglyceridemia have increased synthesis rates for both cholate and chenodeoxycholate (20). Bile salt synthesis rates are not appreciably changed when nicotinic acid feeding lowers plasma cholesterol concentrations (20). Synthesis rates may also be affected by thyroid hormones. Cholic acid synthesis is decreased and half-life prolonged in hypothyroid subjects. These alterations may be corrected with thyroid hormone (21). Bile acid synthesis is increased in thyrotoxicosis (21). 

Since, in the rat, cholesterol is eliminated largely in the form of bile acids, it was expected that bile acid secretion in bile would be increased in the hyperthyroid state. Early experiments to test this point indicated that biliary bile acid secretion was actually normal or below normal (2,3). These results can be explained in terms of the inadequate analytical procedures then in use. Only cholate secretion was measured, and the levels of cheno-deoxycholate were not taken into account. When both of these bile acids were determined, it was shown that, in the bile fistula rat, the total production of bile acids was about the same in the hyperthyroid as in the euthyroid state, and lower in the hypothyroid state (4). In addition, in the hyperthyroid state, the normal ratio of cholate/chenodeoxycholate was reversed from approximately 3 1 to 1 3—cholic acid synthesis was decreased, and chenodeoxycholic acid synthesis was increased two- to threefold (4). Identical results were obtained in the bile fistula rat treated with noncalorigenic doses of D-tri-iodothyronine (5,6), suggesting that these effects are not necessarily a function of the basal metabolic rate. 

More recently, it has been shown that the 12a-hydroxylation of 7a-hydroxycholest-4-en-3-one (an intermediate in cholic acid synthesis) is increased in homogenates from hypothyroid rats and decreased in homogenates from hyperthyroid rats (18). Thyroid hormone, therefore, may exhibit a specific inhibitory effect on the hydroxylation of 7a-hydroxycholest-4-en-3-one. This could explain, in part, the increased chenodeoxycholate... 

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...

A closer analysis of bile acid metabolism with the isotope dilution technique has shown that the low bile acid production in hypercholesterolemia is mainly due to low cholic acid synthesis. This may be related to low hepatic cholesterol synthesis because the cholic acid and cholesterol synthesis rates appear to be interrelated. Cholestyramine actually increases cholic acid synthesis especially in hypercholesterolemic subjects with a low basal cholic acid and cholesterol production. Table 2 shows that the relative amount of cheno is actually quite high in hypercholesterolemic subjects and is lowered by cholestyramine in most subgroups. 

Figure 1.1 illustrates a condensed version of the classical pathway of bile-acid synthesis, a series of 12 enzymatic reactions that convert cholesterol, which is insoluble, into BAs, which are water soluble. The cholesterol is first converted to 7 alpha-hydroxy cholesterol, followed by the series of enzymatic transformations, eventually producing cholic and chenodeoxycholic acids (not all steps shown). The rate-limiting enzyme in this pathway is cholesterol 7 alpha-hydroxylase (CYP 7A1), which originates from microsomal cytochrome P-450 enzymes, expressed only in the liver hepatocytes. 

Stereospecific ketone reduction was also observed (Giordano et al. 1985) with potassium, rubidium, and cesium (but not with sodium) in tertiary alcohols (but not in secondary or primary alcohols). The undesirable dimerization probably proceeds more readily in the case of sodium. Tertiary alcohols are simply more acidic than primary or secondary alcohols. It is reasonable to point out that the ketone-to-alcohol reduction of 3a-hydroxy-7-oxo-5p-cholic acid by alkali metals is a key step in the industrial synthesis of 3a,7p-dihydroxy-5p-cholic acid. 

In approaches to a synthesis of quassinoids, the ketone (124), derived from cholic acid, has been converted into the lactone (125), with the C-7 stereochemistry of quassinoids. ... 

Cholic acid may be converted in several steps into the 3,9-epoxy-carboxyIic acid (246) which has the ABC ring system of batrachotoxin. The synthesis of 24-nor-5a-cholic acid from methyl cholate involved the Barbier-Wieland degradation of the side-chain and treatment of the resultant 24-nor-5/3-cholic acid with Raney nickel. A major product of this reaction was the 5a-3-oxo-compound (247) which... 

There was no relationship between rate of synthesis or hepatic content of ubiquinone in the rat and the production and excretion of p-hydroxybenzoate.393 Exposure to low temperatures caused an increase in ubiquinone synthesis, whilst starvation or feeding with cholesterol or cholic acid resulted in a reduction of the conversion of p-hydroxybenzaldehyde into ubiquinone no feedback by the end-product seemed to be operative. 

Thiol esters have recently found broad applications in organic synthesis. Two methods for their preparation from acid chlorides and acids are described in the preparation of 2-METHYLPROPANE-2-THIOL ESTERS OF CYCLOHEXANECARBOXYLIC ACID AND CHOLIC ACID. Conversion of the former thiol ester to the corresponding O-t-butyl ester illustrates a general method for the preparation of O-ESTERS FROM THE CORRESPONDING THIOL ESTERS. 

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