Chenodeoxycholate synthesis

In 3-oxosteroid A4-steroid 5)3-reductase deficiency, key intermediates for cholic and chenodeoxycholic synthesis, 7a-hydroxy-4-cholesten-3-one and 7a,12a-dihy-droxy-4-cholesten-3-one undergo side-chain oxidation and conjugation to produce... 

Chenodeoxycholate synthesis may possibly proceed along several pathways. As shown in Fig. 2, one route is similar to that for cholate, in which ring alterations are completed before side-chain oxidation. A second suggested route begins with the oxidation of a terminal methyl group of cholesterol, yielding 26-hydroxycholesterol (9,10), which is readily converted to chenodeoxycholate but not cholate in the rat. Such a route involving 26-hydroxy-cholesterol remains speculative in man, however, as this compound has not yet been identified as a metabolite of cholesterol in human bile and there is some recent evidence that 26-hydroxycholesterol is not an important intermediate in bile salt formation (11). 

The rate of cholate synthesis in man is about 200-300 mg/day, as measured by isotope dilution studies. The chenodeoxycholate synthesis rate is similar, so that the total primary bile salt synthesis is about 400-600 mg daily for a healthy adult, and when in the steady state this amount is also the daily fecal excretion rate (12). 

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. 

Kandell and Bernstein published one of the earliest reports to suggest that bile acids also demonstrate DNA-damaging effects in eukaryotic cells. They showed that human foreskin fibroblasts underwent unscheduled DNA synthesis (indicating DNA repair), as measured by tritiated thymidine incorporation when cells were treated with increasing concentrations of sodium deoxycholate or chenodeoxycholate. Utilising mutant Chinese hamster ovary cells deficient in strand rejoining (EM9), the authors were able to demonstrate that the repair of deoxycholate-induced DNA damage was dependent on strand break repair capacity. 

Fig. 9. The elaboration of the cholesteol nucleus in bile acid synthesis. (Cholic acid and chenodeoxycholic acid biosynthesis pathway).

Finally, treatment of these patients with chenodeoxycholic acid (750 mg per day) decreased cholestanol production and plasma concentrations of bile alcohols and suppressed abnormal bile acid synthesis (70). 

Patients also develop cholesterol gallstones from a defect in bile acid synthesis. The defect is in the mitochondrial C27-steroid 27-hydroxylase. In these patients, the reduced formation of normal bile acids, particularly chenodeoxycholic acid, leads to the up-regulation of the rate limiting enzyme Tct-hydroxylase of the bile acid synthetic pathway (discussed later). This leads to accumulation of 7a-hydroxylated bile acid intermediates that are not normally utilized. 

The exact contributions of these alternate pathways to total hepatic bile acid synthesis in normal subjects is not certain, although 26-hydroxylation is usually regarded as the major pathway. In addition, it should be pointed out that current views of hepatic cholic acid and chenodeoxycholic acid synthesis are based primarily oh studies carried out in the rat. More recent studies, which have involved the administration of labeled bile acid intermediates to patients, have suggested that bile acid biosynthesis is more complex than previously thought and that multiple pathways exist to convert cholesterol to bile acids (Vll). 

Other clinical signs consist of progressive neurologic dysfunction, cataracts, and premature atherosclerosis (SI). The disease is inherited as an autosomal recessive trait, but is usually only detected in adults when cholesterol and cholestanol have accumulated over many years (S2). Biochemical features of the disease include striking elevations in tissue levels of cholesterol and cholestanol and the presence of unusual bile acids, termed bile alcohols, in bile. These bile alcohols are mainly 5 -cholestane-3a,7a,12a,24S, 25-pentol, Sp-diolestane-3a,7a,12a,23 ,25-pentol and 5P-du)lestane-3a,7a,12a,25-tetrol (S2). As chenodeoxycholic acid is deficient in the bile of patients with CTX, it was postulated that early bile salt precursors are diverted into the cholic acid pathway and 12a-hydroxy bile alcohols with an intact side chain accumulate because of impaired cleavage of the cholesterol side chain and decreased bile acid production (S2). HMG-CoA reductase and cholesterol 7a-hydroxylase activity are elevated in subjects with CTX (N4, N5), so that sufficient 7a-hydroxycholesterol should be available for bile acid synthesis. 

Using this technique, pool sizes of cholic acid and chenodeoxycholic acid have been estimated to be similar and around 1.0 to 1.5 g each in healthy subjects, with the total bile acid pool amounting to 2 to 4 g (H18, LIO, VIO). Cholic acid turnover is more rapid than for chenodeoxycholic acid, and the rate of hepatic synthesis of cholic acid (300 to 400 mg/day) is therefore approximately double that for chenodeoxycholic acid (150 to 200 mg/day) (H18, VIO). In the steady state, total bile acid synthesis by the liver should equal bile acid loss in the feces, which is around 400 mg/day. Some studies have found that estimates of bile acid synthesis by the isotope dilution technique give values that are higher than those obtained by direct chemical measurement of fecal bile salts (S45), but good agreement has recently been claimed between the two methods (DIO). ITie Lindstedt technique for measuring bile acid turnover and pool size has been modified so that only one bile sample need be collected after intravenous administration of the labeled bile acid. These modified methods measure either pool size alone (D9) or pool size and turnover if both and bile acid are administered at an interval of 24 hours apart (V6). 

Recent investigations into the mechanism of action of these bile acids indicate that ursodeoxycholic acid has certain advantages over chenodeoxycholic acid in the context of the overall homeostasis of cholesterol metabolism (F6). In contrast to chenodeoxycholic acid, ursodeoxycholic acid does not suppress bile acid synthesis (H7), possibly because the a-orientation of the 7-hydroxyl group of chenodeoxycholic acid is required to inhibit cholesterol 7a-hydroxylase activity. Thus, cholesterol breakdown into bile acids is not reduced by ursodeoxycholic acid. Other favorable factors are that ursodeoxycholic acid has a reduced capacity to solubilize cholesterol into micellar solution compared to chenodeoxycholic acid and intestinal cholesterol absorption is decreased by this bile acid (F6, H7). However, in gallbladder bile the relative limitation of ursodeoxycholic acid for micellar solubilization of cholesterol is compensated for by an ability to transport... 

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