Sterol metabolism. XXIII. Cholesterol oxidation by radiation-induced processes

Smith, Leland L.; Teng, Jon I.; Kulig, Martin J.; Hill, Freddie L.

doi:10.1021/jo00949a041

Cited by 123 publications

(53 citation statements)

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“…The singlet oxygen mechanism is characterized by the formation of the epimeric 6-hydroperoxides (main product), which readily rearrange to form epimeric 7-hydroperoxides (7OOCh) ( 28 ). 7OOCh is reactive and will oxidize other molecules and rearrange, becoming epimeric 7HCh and 7KCh (33)(34)(35). The singlet oxygen mechanism requires light and a suitable photosensitizer to capture the light and oxidize the cholesterol.…”

Section: Nonenzymatic Oxidationmentioning

confidence: 99%

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

Rodríguez

Larráyoz

2010

Journal of Lipid Research

121

115

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Journal of Lipid Research Volume 51, 20102847 their actions affect the retina and the retinal pigment epithelium (RPE) ( 8-10 ). One particular oxysterol, 7-ketocholesterol (7KCh), has been found more abundantly than other oxysterols in the retina ( 9, 10 ). This oxysterol is known to have potent pharmacological properties that lead to infl ammation and cell death in a variety of cell types ( 1-10 ). This review will focus on what is known about this molecule and the potential implications of its presence in the retina. The retina is a light-capturing tissue that contains at least 5 cell classes and more than 50 different cell types, each performing unique functions that ultimately provide the visual centers in the brain the information to achieve image formation and visual perception. The retina faces a unique photooxidative environment that generates challenges not encountered by other neurological tissues or organs. Phototransduction requires the retina to have a high metabolic rate ( 11 ) and multiple and complex membrane structures ( 12 ). The photoreceptor outer segments are enriched in the highly photosensitive docosahexaenoic acid and other Abstract This review will discuss the formation and potential implications of 7-ketocholesterol (7KCh) in the retina. 7KCh is a proinfl ammatory oxysterol known to be present in high amounts in oxidized LDL deposits associated with atheromatous plaques. 7KCh is generated in situ in these lipoprotein deposits where it can accumulate and reach very high concentrations. In normal primate retina, 7KCh has been found associated with lipoprotein deposits in the choriocapillaris, Bruch's membrane, and the retinal pigment epithelium (RPE). In photodamaged rats, 7KCh has been found in the neural retina in areas of high mitochondrial content, ganglion cells, photoreceptor inner segments and synapses, and the RPE. Intermediates found by LCMS indicate 7KCh is formed via a free radical-mediated mechanism catalyzed by iron. 7KCh seems to activate several kinase signaling pathways that work via nuclear factor B and cause the induction of vascular endothelial growth factor, interleukin (IL)-6, and IL-8. There seems to be little evidence of 7KCh metabolism in the retina, although some form of effl ux mechanism may be active. The chronic mode of formation and the potent infl ammatory properties of 7KCh indicate it may be an "age-related" risk factor in aging diseases such as atherosclerosis, Alzheimer's, and age-related macular degeneration. -Rodríguez, I. R., and I. M. Larrayoz. Cholesterol oxidation in the retina: implications of 7-KCh formation in chronic infl ammation and age-related macular degeneration. J. Lipid Res . 2010. 51: 2847-2862. Supplementary key words 7-ketocholesterol • cytokines • oxysterolsIn the past year, numerous reviews have been published that extensively discuss the multiple functions of oxysterols and their complex relationships to diseases ( 1-7 ). However, the formation and function of oxysterols in the retina has not been well studied. Emerging studies are...

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Section: Nonenzymatic Oxidationmentioning

confidence: 99%

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

Rodríguez

Larráyoz

2010

Journal of Lipid Research

121

115

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“…Cholesterol photoproducts were analyzed by TLC, using adaptations of previously published methods (18,19). The typical procedure was as follows.…”

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confidence: 99%

Photodynamic action of merocyanine 540 on artificial and natural cell membranes: involvement of singlet molecular oxygen.

Kalyanaraman¹,

Feix²,

Sieber³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

134

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The photochemistry of merocyanine 540 (MC 540), a sensitizing dye that binds preferentially to leukemia and electrically excitable cells, has been investigated. MC 540-mediated photooxidation of histidine, arachidonate, and unsaturated phospholipid vesicles was assessed by spin label oximetry and shown to involve type II (singlet oxygen) chemistry. The dye was also shown to be a potent sensitizer of lipid peroxidation in a natural cell membrane, the erythrocyte ghost. Inhibition by azide, stimulation by 2H20, and identification of the cholesterol product 5a-cholest-6-ene-3,8,5-diol in this system, all were consistent with singlet oxygen intermediacy. Finally, MC 540 was found to be considerably more phototoxic to-K-562 leukemia cells in 2H20 than in H20. We conclude that singlet oxygen plays a major role in the phototherapeutic effects of this dye. (4)(5)(6)(7)(8). In this way leukemic cells have been selectively purged from bone marrow in vitro, and attempts to exploit this differential photosensitivity in clinical situations are underway (9).Although the effectiveness of MC 540 in killing neoplastic cells has been demonstrated (5-8), little is known about the mechanism of cell killing, and those factors on which the selectivity of MC 540 for cancer cells is based are not understood. However, the fact that uptake and toxicity of MC 540 in leukemic cells are augmented in the presence of visible light and oxygen (2) suggests that photodynamic processes are involved. A preliminary report has indicated that singlet oxygen (102) is one of the reactive intermediates (10). The first detectable event following the production of this species is rapid consumption of molecular oxygen, which can occur as a result of reactions with biological constituents. Thus, we have used the highly sensitive spin label oximetric approach (11, 12) to monitor oxygen consumption during MC 540-sensitive photooxidation. Using this approach, we now report additional evidence for the production of 102 by the photoactivated dye. The involvement of 102 in the killing of leukemic cells and in the peroxidation of cell membrane phospholipids and cholesterol is also reported. MATERIALS AND METHODSOximetry Studies Using Model Systems. Sample preparation. MC 540 obtained from Eastman was dissolved in a 50:50 mixture of ethanol and water and frozen until further use. Arachidonic acid (Sigma) was dissolved in ethanol. All other chemicals were used as received.Sample irradiation. Samples for irradiation typically contained 90 ,uM MC 540 in deionized water, pH 7.0. 3-Carbamoyl-2,2,5,5-tetramethyl-3-pyrrolin-1-yloxy(CTPO; Aldrich) was added to give a final concentration of 1.2 X 10-4 M. Samples, following saturation with a mixture of 50% nitrogen and 50% air from calibrated flow meters (Matheson) were introduced into a Pasteur pipette, which was sealed with capillary tube sealant (Miniseal, American Scientific Products, Stone Mountain, GA) and subsequently positioned inside the electron spin resonance (ESR) cavity.Samples were irradiated in the ES...

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“…The reaction of '02 with cholesterol results primarily in the production of the Sa-hydroperoxide of cholesterol (10). Radical oxidations, such as those by O2--, produce many different products (primarily the 7a-and 7,Bhydroperoxides), but have never been shown to produce the 5a-hydroperoxide (19). Therefore, positive identification of the Sahydroperoxide after reaction of cercosporin with cholesterol in the light provides strong evidence that '02 is generated by cercosporin.…”

mentioning

confidence: 99%

Light-Induced Production of Singlet Oxygen and Superoxide by the Fungal Toxin, Cercosporin

Daub¹,

Hangarter²

1983

Plant Physiol.

148

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Cercosporin, a toxin produced by members of the fungal genus Cercospora, is a photosensitizing compound which rapidly kills plant cells in the light. We have found that cercosporin, when activated by light in the presence ofoxygen, is able to generate both singlet oxygen and superoxide ions. Cercosporin, when illuminated in the presence of 02, reacted with cholesterol to form the Sa-hydroperoxide of cholesterol which is only produced by reaction with singlet oxygen. Cercosporin, in the presence of light, 02, and a reducing substrate, was also able to reduce p-nitro blue tetrazolium chloride, a compound readily reduced by superoxide. Superoxide dismutase, a scavenger of superoxide, inhibited this reaction. Production of both singlet oxygen and superoxide by cercosporin must be considered when studying the possible mechanisms of resistance to cercosporin.

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Sterol metabolism. XXIII. Cholesterol oxidation by radiation-induced processes

Abstract: The common cholesterol oxidation products 3/3hy dr oxy cholest-5-en-7-one (IV), cholesta-3,5-dien-7one (V), and the epimeric cholest-5-ene-3/3,7-diols

Cited by 123 publications

References 1 publication

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

Photodynamic action of merocyanine 540 on artificial and natural cell membranes: involvement of singlet molecular oxygen.

Light-Induced Production of Singlet Oxygen and Superoxide by the Fungal Toxin, Cercosporin

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