26- Hydroxylation bile acid biosynthesis

CYP27A1 catalyzes the side chain oxidation (27-hydroxylation) in bile acid biosynthesis. Because bile acid synthesis is the only elimination pathway for cholesterol, mutations in the CYP27A1 gene lead to abnormal deposition of cholesterol and cholestanol in various tissues. This sterol storage disorder is known as cerebrotendinous xanthomatosis. CYP27B1 is the 1-alpha hydroxylase of vitamin D3 that converts it to the active vitamin form. The function of CYP27C1 is not yet known. 

CYP27 3 3 Bile acid biosynthesis, vitamin D3 hydroxylations... 

Research on the mechanism of the onset of hypercholesterolemia during a state of marginal vitamin C deficiency (6,21,22) has led to the finding that ascorbate is necessary for cholesterol transformation to bile acids (23) at the rate-limiting reaction of bile-acid biosynthesis. That limiting step is the 7 -hydroxylation of cholesterol (6,24r-26). The action of ascorbate on 7 -hydroxylation is not a direct one because in vitro added L-ascorbic acid has no effect (24,27). The effect is mediated by the intervention of ascorbate in the metabolism of cytochrome P450 in the endoplasmatic reticulum of the hepatal cell (6,24), Through a... 

During bile acid biosynthesis, modifications to the cyclopentanophen-anthrene (steroid) nucleus are thought to precede the oxidation and cleavage of the cholesterol side chain. The first and rate-controlling step in bile acid synthesis is the 7o-hydroxylation of cholesterol (I) to form 7a-hydroxy-choles-terol (II) (Fig. 3). This step is catalyzed by cholesterol 7a-monooxygenase (cholesterol 7a-hydroxylase) (EC 1.14.13.17), a microsomal enzyme (M37). Further metabolism of 7a-hydroxy-cholesterol involves oxidation of the 3p-hydroxyl group and isomerization of the double bond from C-5,6 to C-4,5,... 

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). 

Cholic acid differs from chenodeoxycholic acid in having an extra hydroxyl group at C-12. The enzyme responsible for producing this difference, 7a-hydroxy-4-cholesten-3-one 12a-hydroxylase, thus acts at a key branch point in the biosynthesis of bile acids and might be expected to be regulated in order to control the relative amounts of cholic acid and chenodeoxycholic acid produced. Like other hydroxylation steps in bile acid biosynthesis, 12a-hydroxylation requires a specific form of cytochrome P-450, which is present in the cytochrome P-45OLM4 fraction of rabbit liver microsomes (H6). The activity of I2a-hydroxylase has been postulated to be decreased in patients with liver cirrhosis to explain the low proportion of cholic add relative to chenodeoxycholic add in the bile of these patients (V9). Conversely, the activity of this enzyme may be high in patients with cerebrotendinous xanthomatosis, as the bile of these individuals contains mostly cholic acid... 

The possibUity of multiple pathways in bile acid biosynthesis in man has been discussed by Vlahcevic et al. [180-182]. A number of labelled 7 -hydroxylated intermediates in bile acid biosynthesis were administered to bile fistula patients as well as patients with an intact enterohepatic circulation. In accordance with previous work with bile fistula rats, the spedfic activity of the isolated chohc add was in general considerably lower than that of chenodeoxychohc acid. On the basis of this finding, it was suggested that a portion of chohc acid was synthesized via a route not involving initial 7a-hydroxylation of cholesterol. It must then be assumed that the administered intermediate mixes with the endogenous pool of the same steroid. However, due to compartmentation, the metabolic fate of a precursor reaching the hepatocyte might be different from that of the the same compound formed within the cell. Normally, the different precursors are present in the cells in trace amounts... 

The regulation of the overall biosynthesis of bile acids has been studied intensively during the last decade, and only a small fraction of all the pubhcations can be reviewed here. Cholesterol 7a-hydroxylase is the rate-limiting enzyme in the biosynthesis of both chohc acid and chenodeoxycholic acid. The publications in which a correlation has been demonstrated between bile acid biosynthesis and 7a-hydroxyl-ation of cholesterol have been reviewed by Myant and Mitropoulos [59]. In the present review, emphasis will be put on the feedback regulation of the cholesterol 7a-hydroxylase by the bile-acid flux through the hver, the relation between HMG-CoA reductase and cholesterol 7 -hydroxylase and possible mechanisms for the regulation. 

Angelin et al. reported recently that treatment with a bile-salt-sequestering agent reduced the postprandial but not the fasting serum bile acid levels in human [219]. It was concluded that the postprandial bile acid inflow to the liver may be more important as a regulator of bile acid biosynthesis than the fasting level of bile acids, supporting the contention that a certain concentration of bile acids must be reached in the portal blood to obtain an efficient inhibition of the cholesterol 7a-hydroxyl-ase. 

G. Xu, E. Leitersdorf et al. (2001). Side chain hydroxylations in bile acid biosynthesis catalyzed by CYP3A are markedly up-regulated in Cyp27 mice but not in cerebrotendinous xanthomatosis. 

One of the most important enzymes of type A is the hepatic cholesterol 7a-hydroxylase, which catalyzes 7a-hydroxylation of cholesterol [16]. This is the initial and rate-determining reaction in mammalian bile acid biosynthesis. This enzyme is located only in the liver. 

Also included in this report, are two documented alternative biochemical pathways which are known to introduce oxygen functionaly at C-25 (and C-26) directly without using the oxysterol pathway . In the first, sterols may be hydroxylated at C-25 in the liver during bile acid biosynthesis (1). In the second, vitamin D3 is known to be hydroxylated directly at C-25 in mammalian systems (1). These documented instances occur in the animal kingdom. Plant metabolism, especially the biosynthesis of secondary plant metabolites, has not been examined in sufficient detail to indicate the extent to which direct introduction of a hydroxyl group at C-25 might occur. However, a great deal of evidence is available to indicate that many of these side chain oxysterols are produced via the oxysterol pathway . 

Bile salts are exclusively synthesized in the liver (see A). The slowest step in their biosynthesis is hydroxylation at position 7 by a 7-a-hydroxylase. Cholic acid and other bile acids inhibit this reaction (end-product inhibition). In this way, the bile acids present in the liver regulate the rate of cholesterol utilization. 

The current RDA for vitamin C is 60 mg/day for a healthy non-smoking adult, Vitamin C is a cofactor for several enzymes involved in the biosynthesis of collagen, neurotransmitters, carnitine (45), hydroxylation of cholesterol (to form bile acids). It is also an important water-soluble antioxidant, which scavenges most of the RS and acts as a coantioxidant by regenerating a-tocopheryl radicals (46). 

Salen, G., Shefer, S., Chen, F.W., Dayal, B., Batta, A. K. and Tint, G. S. (1985). Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylation at C-12, C-25, and C-26. J. Clin Invest. 76 744-751. 

Two pathways have been proposed for degradation of the cholestane side chain in the biosynthesis of bile acids. These differ in the site proposed for the first hydroxylation step in side-chain oxidation and are discussed below for the formation of cholic add. 

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