Cholesterol 25-hydroxylase

Scorbutic guinea pigs develop hypercholesterolemia, which may lead to the development of cholesterol-rich gallstones. This is largely the result of impaired activity of cholesterol 7-hydroxylase, which is an ascorbate-dependent enzyme (Section 13.3.8), resulting in reduced oxidation of cholesterol to bUe acids. There is no evidence that increased intakes of vitamin C above requirements result in increased cholesterol catabolism. 

Shefer, S., Gheng, F. W., Hauser, S., Batta, A. K., and Salen, G., Regulation ofbile acid synthesis. Measurement of cholesterol 7 -hydroxylase activity in rat liver microsomal preparations in the absence of endogenous cholesterol. J. Lipid Res. 22, 532-536... 

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. 

Effect of various modifying factors on cholesterol 7 -hydroxylase and HMG-CoA reductase... 

The regulation of cholesterol 7 -hydroxylase may involve some of the following mechanisms ... 

The bile acids returning to the liver in the portal blood inhibit both cholesterol 7a-hydroxylase and HMG-CoA reductase. Size, circulation rate and composition of the bile acid pool are of importance. The inhibitory effect of bile acids on cholesterol 7a-hydroxylase is mediated by an effect on synthesis or breakdown of proteins, most likely the specific species of cytochrome P-450 involved in the hydroxylation. Evidence that the rate of synthesis of the specific species of cytochrome P-450 is of major importance can be obtained only when it is possible to measure accurately the amount of specific cytochrome P-450 by means other than enzyme activity. Although less likely from the data available, it cannot be excluded at the present state of knowledge that the inhibitory effect of bile acids on cholesterol 7a-hydroxylase is mediated by the effect of bile acids on HMG-CoA reductase. Since the substrate pool for cholesterol 7 -hydroxylase does not seem to be affected [59,222], a hitherto unknown mechanism must then be responsible for the coupling between the two rate-limiting enzymes. 

Figure 2. The level of lipoperoxides in the liver microsomes and 7a-cholesterol hydroxylase activity in the same membranes of rabbits and mini-pigs with experimental hypercholesterolemia.

Mast N, White MA, Bjorkhem 1, Johnson EF, Stout CD, Pikuleva lA (2008) Crystal struetures of substrate-bound and substrate-free eytoehrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc Natl Acad Sci U S A 105 9546-9551... 

Pikuleva lA, Mast N, Liao WL, Turko IV (2008) Studies of membrane topology of mitochondrial cholesterol hydroxylases CYPs 27A1 and UAL Lipids43 1127-1132... 

Ascorbic acid is involved in carnitine biosynthesis. Carnitine (y-amino-P-hydroxybutyric acid, trimethylbetaine) (30) is a component of heart muscle, skeletal tissue, Uver and other tissues. It is involved in the transport of fatty acids into mitochondria, where they are oxidized to provide energy for the ceU and animal. It is synthesized in animals from lysine and methionine by two hydroxylases, both containing ferrous iron and L-ascorbic acid. Ascorbic acid donates electrons to the enzymes involved in the metabohsm of L-tyrosine, cholesterol, and histamine (128). 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

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. 

Figure 26-7. Biosynthesis and degradation of bile acids. A second pathway in mitochondria involves hy-droxylation of cholesterol by sterol 27-hydroxylase. Asterisk Catalyzed by microbial enzymes.

Cohen JC. Contribution of cholesterol 7alpha-hydroxylase to the regulation of lipoprotein metabolism. Curr Opin Lipidol 1999 10 303-307. 

Wang J, Freeman DJ, Grundy SM, Levine DM, Guerra R, Cohen JC. Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations. J Clin Invest 1998 101 1283-1291. 

Couture P, Otvos JD, Cupples LA, Wilson PW, Schaefer EJ, Ordovas JM. Association of the A-204C polymorphism in the cholesterol 7alpha-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study. J lipid Res 1999 40 1883-1889. 

Payne AH. Hormonal regulation of cytochrome P450 enzymes, cholesterol side-chain cleavage and 17 alpha-hydroxylase/C 17-20 lyase in Leydig cells. Biol Reprod 1990 42(3) 399-404. 

Matheson, H. B., Colon, I. S., and Story, J. A. (1995). Cholesterol 7a-hydroxylase activity is increased by dietary modification with psyllium hydrocolloid, pectin, cholesterol and cholestyramine in rats. /. Nutr. 125,454-M58. 

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