Cholesterol a-oxide

A review of the properties and uses of cholesterol includes references to such diverse information as complex formation, inclusion in cosmetics, liquid crystals, solubilities, and ice nucleation 265 Carcinogenicity associated with 5,6a-epoxy-5a-cholestan-3/3-ol ( cholesterol a-oxide ) may account for earlier indications that cholesterol samples can contain carcinogens hydroperoxides, including the 7-hydroperoxycholesterols which result from autoxidation, have been shown to epox-idize cholesterol in low yields.266... 

A solution of 1 g. of cholesterol a-oxide in 30 ml. of hot acetone is treated with a solution of 0.625 g. of periodic acid dihydrate in 10 ml. of water." Before all the precipitated oxide has redissolved, thin plates of cholestane-3/3, 5a,6(8-triol begin to separate. The mixture is refluxed for one half hour, cooled, and the product collected yield 0.83 g. (81%), m.p. 231-232°. A second crop of material (0.14 g.) melted at 225-226°. 

Black, H. S., and Douglas, D. R., 1972, A model system for the evaluation of the role of cholesterol a-oxide in ultraviolet carcinogenesis. Cancer Res. 32 2630. 

The outer layer or cortex of the adrenal gland is the source of a large group of sub stances known as corticosteroids Like the bile acids they are derived from cholesterol by oxidation with cleavage of a portion of the alkyl substituent on the D ring Cortisol IS the most abundant of the corticosteroids but cortisone is probably the best known Cortisone is commonly prescribed as an antiinflammatory drug especially m the treat ment of rheumatoid arthritis... 

Oxidization of LDL-cholesterol is believed to play a significant role in the atherosclerotic process. The antioxidant vitamins, vitamin E and vitamin C, protect LDL cholesterol from oxidation. Evidence from observational and animal studies suggested that increased intake of antioxidant vitamins might inhibit the formation of atherosclerotic lesions and decrease the risk for cardiovascular events.40 However, several large, randomized, prospective studies found no beneficial effect of vitamin E or other antioxidants on cardiovascular outcomes in patients with IHD or IHD risk factors.41,42 Based on this evidence, current guidelines do not recommend supplementation with vitamin E or other antioxidants for the sole purpose of preventing cardiovascular events. 

By far the most impressive example of electrophilic addition in natural prodnct formation is in the biosynthesis of steroids. The snbstrate sqnalene oxide is cyclized to lanosterol in a process catalysed by a single enzyme. Lanosterol is then converted into the primary animal-steroid cholesterol. Sqnalene oxide comes from sqnalene, which is itself formed throngh a combination of two molecules of farnesyl diphosphate. 

The best evidences are studies from preclinical animal models [86, 87, 105], or knockout animals lacking appropriate anti-oxidative pathways [106]. For example, Balb/c mice administered a variety of anti-oxidants in their chow were protected from acetaminophen hepatotoxicity [107]. Rats fed with the anti-oxidant melatonin were protected from cholesterol mediated oxidative liver damage [108]. The best clinical evidence that oxidative stress is a key player in a variety of liver injury diseases is the beneficial application of silymarin in these disease indications [109]. Silymarin is a polyphenolic plant fiavonoid (a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin and silichristin) derived from Silymarin maria-num that has antioxidative, antilipid peroxidative, antifibrotic and anti-inflammatory effects [109, 110]. 

Stein, J.H., Keevil, J.G., Wiebe, D.A., Aeschlimann, S., and Eolts, J.D., Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease. Circulation, 100, 1050, 1999. 

The effects of wine and its polyphenol constituents on early indicators of coronary heart disease such as elevated levels of plasma lipids, platelets and serum antioxidant activity were discussed in a review by Cooper et al. (2004). This review also addressed whether the polyphenols or alcohol are responsible for the beneficial effects of wine on cardio-vascular health. The authors conclude that red wine polyphenols have little effect on plasma lipid concentrations, but that wine consumption reduces the susceptibility of low-density lipoprotein (LDL) cholesterol to oxidation and increase serum antioxidant capacity. These effects, however, do depend on the amount of wine that is consumed and the period of supplementation. It was suggested that specific polyphenols appear to have endothelium-dependent vaso-relaxing abilities. Red wine phenolics also have an inhibitory effect on platelet aggregation. Evidence suggests that alcohol has a positive synergistic effect with wine polyphenols on some atherosclerosis risk factors. Thus, evidence that wine drinking is beneficial for cardiac health appears positive. 

Baba, S., Natsume, M., Yasuda, A., Nakamura, Y., Tamura, T., Osakabe, N., Kanegae, M., Kondo, K. (2007a). Plasma LDL and HDL cholesterol and oxidized LDL concentrations are altered in normo- and hypercholesterolemic humans after intake of different levels of cocoa powder. J. Nutr., 137, 1436-1441. 

The cholesterol is oxidized (that is, an electron is removed with the hydrogen atom), so that the double bond is a consequence of 2 mutually shared electrons between carbons 7 and 8. 

As summarized in the previous paragraph, LDL cholesterol is oxidized to various oxysterols due with high cytotoxicity and promoting vascular injury [63]. Oleuropein and a mixture of phenols extracted firom virgin oil inhibited dose-dependently the formation of oxysterols and prevented apoprotein modification in UV irradiated LDL. IC50 are shown in table 4 ... 

Oxidation of sec-alcohols, In the presence of CH3CO3H, this chromium(VI) reagent can be used in catalytic amount (2 mole %) for oxidation of ec-alcohols to ketones in high yield. Under these conditions cholesterol is oxidized to A -3-cholestanone (84% yield). Primary alcohols can be oxidized to aldehydes (—80% yield). r-Butyl hydroperoxide or anhydrous H2O2 cannot replace the peracetic acid as the reoxidant. 

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,... 

M18. Meyer, D. J., and Ketterer, B., 5a,6a-Epoxy-cholestan-3p-ol (cholesterol alpha-oxide) A specific substrate for rat liver glutathione transferase B. FEBS Lett. 150, 499-502 (1982). 

Cholesterol, whether ingested or formed endogenously, provides the starting material for the biosynthesis of all the other steroids found in mammals. Excess cholesterol is oxidized in the hver to polar compounds called cholic acids. This process converts the terminal side chain in cholesterol to a carboxyhc acid and introduces hydroxyl groups. These polyhydroxylated, steroidal acids play a central role in absorption of fats from the intestine and also excretion of superfluous cholesterol. 

Another hydroxylation role for vitamin C in the hepatic microsomal fraction is the stepwise conversion of cholesterol to the bile acid, cholic acid, via 7a-hydroxycholesterol, 3a,7a-dihydroxycoprostane and 3a,7a,12o-trihydroxycoprostane. Also, in lipid metabolism, conventional fatty acids with an even number of carbon atoms are a-oxidised by a mono-oxygenase and subsequently decarboxylated to form an odd-numbered carbon derivative and both these steps appear to require ascorbic acid. As the initial a-oxidation is brought about by a... 

Low-density lipoprotein complexes (LDLs), which are the primary means of transporting cholesterol in the blood, are readily oxidized. These oxidations include peroxidation of unsaturated fatty acids, hydroxylation of cholesterol, and oxidation of amino acid residues in the apoprotein. A class of white blood cells recognizes the oxidation and absorbs the LDL through its scavenger receptor. After a white blood cell has absorbed numerous LDLs containing cholesterol, it becomes engorged and is referred to as a foam cell. Foam cells attract other white blood cells, which leads to accumulation of more cholesterol. Ultimately, this accumulation of cholesterol becomes one of the chief chemical constituents of the atherosclerotic plaque that forms at the site. 

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