24S-Hydroxycholesterol

Li-Hawkins J, Lund EG, Bronson AD, RusseU DW. 2000. Expression cloning of an oxysterol 7alpha-hydroxylase selective for 24-hydroxycholesterol. J Biol Chem 275 16543-16549. 

Another pathway of some importance occurs in the brain this is the cholesterol 24-hydroxylase pathway. About 25% of the body s cholesterol exists in the plasma membranes of myelin sheaths. Here, the blood-brain barrier prevents cholesterol exchanges with the circulating lipoproteins, which makes it difficult for cholesterol to leave the brain. The cytochrome P-450 enzymes (CYP 46), expressed almost exclusively in the endoplasmic reticula of the brain, allows formation of 24-hydroxycholesterol. 

Purification of cholesterol through the dibromide completely eliminates cholestanol, 7-dehydrocholesterol, and latho-sterol (A7-cholestenol). The first crop of material from methanol-ether is also free from cerebrosterol (24-hydroxycholesterol) and 25-hydroxycholesterol, a product of autoxidation present in cholesterol that has been stored in the crystalline state for a few years with access to air. When material of highest purity is desired, only first-crop dibromide should be employed, since de-bromination of second-crop material gives sterol melting at 146-147° and giving a positive Beilstein test. 

Lutjohann D, Papassotiropoulos A, Bjorkhem I, et al. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res 2000 41 195-198. 

The C-24 configurations of the isomeric 24-hydroxy-cholesterols have been firmly established5 by chemical correlation with the known 24R,25- and 24S,25-epoxyderivatives, and by the modified Horeau method.6 With the configurations known, differences in 13C n.m.r. spectra and in polarity were used to establish the configurations of the la,24-dihydroxy-derivatives of vitamin D3.5 Cerebrosterol , isolated from brain tissue, is 24S-hydroxycholesterol,6a but the natural 24,25-dihydroxy-vitamin D3 has the (24R) configuration. The C-24 isomeric 24,25-dihydroxy-cholesterols have also been separated and characterized.7... 

The previously described (24S)-24,25-epoxycholesteryl benzoate has been reduced with lithium aluminium hydride-aluminium chloride to give a chromato-graphically separable mixture of 25-hydroxycholesterol (55%) and (24S)-24-hydroxycholesterol (273),133 the configuration of which was determined by the modified Horeau method.135 It is interesting to note that cerebrosterol isolated from brain is (24S)-24-hydroxycholesterol whereas natural 24,25-dihydroxy-vitamin D3... 

Asymmetric reduction of 2i-24-oxosteroids. Reduction of the unsaturated 24-oxosteroid 2 with LiAlH4 and the (R)-( + )-isomer of Noyori s reagent (1) gives a mixture of the two diols 3 and 4 in the ratio 95 5. The stereoselectivity is reversed by use of (S)-(—)-l. This reaction was used to prepare optically pure (24R)- and (24S)-24-hydroxycholesterol and the epimeric pairs of 24,25-dihydroxycholesterol and 25,26-dihydroxyeholcsterol.2... 

Nuclear receptor agonists/Liver X Receptor (LXR) agonists 24S -Hydroxycholesterol 27-Hydroxycholesterol GW3965 T0901317... 

S-hydroxycholesterol, a CYP46 enzyme derived metabolite, crosses the BBB [100,129] and levels have been reported to be elevated in early AD [130-... 

Some studies have also suggested that CYP46A1 polymorphisms may be linked to AD [135-145]. As discussed previously, 24S-hydroxycholesterol is an important regulator of ApoE -mediated cholesterol transfer from astrocytes to glia and excess 24S-hydroxycholesterol may be neurotoxic and pro-inflammatory [100,111,146-148]. Reports regarding statin effects on 24S-hydroxycholesterol have been mixed. Some studies demonstrated decreases in 24S-hydroxycholesterol levels following statin treatment [90,149,... 

Modest decreases in 24S-hydroxycholesterol may have benefit on brain function by reducing ApoE levels which have been reported to potentially impede LIP and stimulate the phosphorylation of tau. 

J23-22-Acetoxycholcstcrol derivatives can be converted stereoselectively with bis(aceto-nitrile)dichloropalladium(II) as a catalyst to 24-hydroxycholesterol derivatives435. The (225,23 )- and (225,23Z)-diastereomers react more rapidly than the (22i ,23 >isomer, and the (22i ,23Z)-compound does not rearrange under the reaction conditions. The difference in the reactivity is attributed to the different conformations of the side chains of the 22-hydroxy-cholesterol derivatives, as the coordination of the palladium complex with the 7t-electrons of the double bond from the side opposite the acetoxy group is sterically hindered in the less reactive derivative. 

The existence of an alternate pathway for the synthesis of bile acids was suspected because it was possible for oxysterols to be converted into bile acids (N. Wachtel, 1968). It is now recognized that a variety of oxysterols produced by an assortment of cell types can be converted into bile acids. The production of these oxysterols is catalyzed by several sterol hydroxylases sterol 27-hydroxylase (CYP27A1) (J.J. Cali, 1991), cholesterol 25-hydroxylase (CH25H) (E.G. Lund, 1998), and cholesterol 24-hydroxylase (CYP46A1) (E.G. Lund, 1999). Cholesterol 25-hydroxylase is not a cytochrome P-450 monooxygenase, unlike the two other enzymes. Almost all of the 24-hydroxycholesterol that ends up in the liver originates from the brain, and it has been suggested that the production of... 

Epoxy cholesterol 24-Hydroxycholesterol Role in lipid and cholesterol metabolism atherosclerosis... 

The classic reaction of P450 7A1 is cholesterol 7a-hydroxylation, and esterified cholesterol is not a substrate . However, recent experiments have established that the enzyme also catalyzes the 7a-hydroxylation of 24-hydroxycholesterol, with preference for the (5)-isomer . 7a-Hydroxylation (with recombinant human P450 7A1) was observed with 20(5)-hydroxycholesterol, 25-hydroxycholesterol, and... 

An expression-cloning approach was utilized to isolate a cDNA from Cyp7bl ) mice that could, when expressed, catalyze the 7a-hydroxyla-tion of 24-hydroxycholesterol . P450 39 has a microsomal location with a preference for the substrate 24-hydroxycholesterol and is expressed in liver. Presumably these characteristics of mouse P450 39 apply to the human ortholog but no further information is yet available. Potential relevance of this enzyme is in the inactivation of... 

The significance of P450 46A1 rests in the fact that the brain is the most cholesterol-rich tissue in the body . LXRs, members of the nuclear hormone receptor family, are activated by 24-hydroxycholesterol. LXR 3 and P450 46 have overlapping expression patterns in brain. The system may be counter-balanced by P450 39, which catalyzes the 7a-hydroxylation of... 

Weiner MF, Vega GL, Diaz-Arrastia R, Moore C, Madden C, Hudak A, Liitjohann D (2008) Plasma 24S-hydroxycholesterol and other oxysterols in acute closed head injury. Brain Inj 22 611-615... 

---