7p-hydroxycholesterol

The toxic effect of 7-oxysterols, 25- and 27-hydroxycholesterols and their involvement in LDL cytotoxicity have been extensively studied on the different vascular cell types (Lizard et al, 1999 Aupeix et al, 1995 Clare et al, 1995 Ramasamy et al, 1992). 7a and 7p-hydroxycholesterols, 7-ketocholesterol, 25 and 27-hydroxycholesterol induce apoptosis (Brown and Jessup, 1999 Lizard et al, 1999, 1998 Zhang et al, 1997 Hughes et al, 1994). 7p-hydroperoxycholesterol is one of the most toxic Oxysterols present in oxidized LDL (Brown and Jessup, 1999 Colles et al, 1996). 25-hydroxycholesterol, though less active (Aupeix et al 1995), is able to trigger a cytochrome c release and subsequent caspase activation in CHO cells, but also calcium inaease in relation with apoptosis (Rusinol et al, 2000). 

In follow-up to these findings with brain injury, the experiment program with LCM was expanded to next examine the use of LCM to deliver 7P-hydroxycholesterol (7P-OHC) to a radiofrequency (thermal) lesion in the rat brain. With diO-labeled LCM, it was first reaffirmed that LCM target the injury area specifically and not the adjacent normal tissue. With immuno-histochemistry and fluorescent immunochemistry, it was then demonstrated that the 7(3-0 HC, delivered in LCM, exerts an antigliosis effect in the rat brain injury model (ref 534) (see below). 

A. Kupferberg, G. Teller, P. Behr, C. Leray, P.F. Urban and G. Vincendon, Effect of 7p-hydroxycholesterol on astrocyte primary cultures and derived spontaneously transformed cell lines cytotoxicity and metabolism, Biochim. Biophys. Acta 1013 (1989)231-238. 

The oxysterol 7-ketocholesterol is an important COP involved in atherosclerotic lesions and macrophage foam cells (275). There is no direct evidence in humans that COPs contribute to atherogenesis, but it has been found that COP levels are elevated in LDL subfractions that are considered potentially atherogenic (276). In addition, raised levels of 7p-hydroxycholesterol may be associated with an increased risk of atherosclerosis. Arterial injury by COPs causes endothelial dysfunction and arterial wall cholesterol accumulation (277). Even under normocholesterolemic conditions, COPs can cause endothelial dysfunction, increased macromolecular permeability, and increased cholesterol accumulation. These are all factors believed to be involved in the development of atherosclerotic lesions. The atherogenic potential of COPs has been demonstrated by in vitro cell culture (73, 278), as well as in animal feeding studies (279). Japanese quail fed either purified cholesterol or oxidized cholesterol exhibited greater plasma and liver cholesterol concentrations in association with increased severity of atherosclerotic lesions when fed the oxidized cholesterol (279). 

Although cholesterol is widely distributed in the various body tissues, it is found in highest concentration within the central and peripheral nervous systems. Other sterols such as cholestanol, 7-dehydrocholesterol, latho-sterol, 24-hydroxycholesterol, 7a- and 7P-hydroxycholesterol have also been detected in nervous tissue, but their contribution to the total sterol content of the brain is certainly small they will not be considered in the present review. Desmosterol and esterified cholesterol are present in developing brain but in normal adults only unesterified cholesterol is found. Cholesterol accounts for about 10% of the dry weight of the brain in contrast to less than 1% found in most other organs. This high concentration of cholesterol seems to be characteristic of nervous tissue,... 

Maguire L, Konoplyannikov M, Lord A, Maguire AR, O Brien NM (2003) Comparison of the cytotoxic effects of P-sitosterol oxides and a cholesterol oxide, 7P-hydroxycholesterol, in cultured mammalian cells. Br J Nutr 90(4) 767-775. doi 10.1079/BJN2003956... 

D. Bochelen, F. Eclancher, A. Kupferberg, A. Privat and M. Mersel, 7(5-hydroxycholesterol and 7p-hydroxycholesteryl-3-esters reduce the extent of reactive gliosis caused by an electrolytic lesion in rat brain, Neuroscience 51 (1992) 827-834. 

Several oxysterol classes present in oxLDL appear to be cytotoxic toward fibroblasts, ECs, and vascular smooth muscle cells, especially 7-hydroperoxycholes-terol (7-OOH-chol), 7P- and 7a-hydroxycholesterol (7-OH-chol), 7-ketocholesterol (7-keto-chol), and cholesterol epoxides (epoxy-chol). 7p-OOH-chol, a precursor of hydroxyl- and keto-oxysterols, was reported to be the most toxic. During LDL oxidation 7P-OOH-chol was produced in three to five times higher quantities than 7a-OOH-chol, other oxysterols and even hydroxy-nonenal, which is one of the most abundant lipid oxidation products. Cytotoxicity of oxysterols was connected to increased cellular oxidative stress. Some studies suggest that oxysterols are even involved in oxidative stress induction. Animal models indicate that dietary oxysterols can significantly decrease glutathione levels and increase expression of glutathione peroxidase and superoxide dismutase. In apolipoprotein-deficient mice, the NADPH-oxidase activity was induced by 7-keto-chol, 7p-OH-chol, and Sp,6P-epoxy-chol. The increased activity of NADPH oxidase yields more superoxide anions that amplify oxidative stress. 

Sevanian et al. (1994) applied GLC and LC/TS/MS for the analysis of plasma cholesterol-7-hydroperoxides and 7-ketocholesterol. Analysis of human and rabbit plasma identified the commonly occurring oxidation products, yet dramatic increases in 7-ketocholesterol and cholesterol-5p, 6P-epoxide were observed. The study failed to reveal the presence of choles-terol-7-hydroperoxides, which were either too unstable for isolation, metabolized or further decomposed. The principal ions of cholesterol oxides monitored by LC/TS/MS were m/z 438 (cholestane triol) m/z 401 (cholesterol-7-hydroperoxide) m/z 401 (7-ketocholesterol) m/z 367 (7a-hydroxycholesterol) m/z 399 (cholesta-3,5-dien-7-one) and m/z 385 (choles-terol-5a,6a-epoxide). The major ions were supported by minor ions consistent with the steroid structure. Kamido et al. (1992a, b) synthesized the cholesteryl 5-oxovaleroyl and 9-oxononanoyl esters as stable secondary oxidation products of cholesteryl arachidonate and linoleate, respectively. These compounds were identified as the 3,5-dinitrophenylhydrazone (DNPH) derivatives by reversed-phase LC/NICI/MS. These standards were used to identify cholesteryl and 7-ketocholesteryl 5-oxovaleroyl and 9-oxononanoyl esters as major components of the cholesteryl ester core aldehydes generated by copper-catalysed peroxidation of low-density lipoprotein (LDL). In addition to 9-oxoalkanoate (major product), minor amounts of the 8, 9, 10, 11 and 12 oxo-alkanoates were also identified among the peroxidation products of cholesteryl linoleate. Peroxidation of cholesteryl arachidonate yielded the 4, 6, 7, 8, 9 and 10 oxo-alkanoates of cholesterol as minor products. The oxysterols resulting from the peroxidation of the steroid ring were mainly 7-keto, 7a-hydroxy and 7P-... 

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