Cytochrome P450 and gene activation—from pharmacology to cholesterol elimination and regression of atherosclerosis

Luoma, P. V.

doi:10.1007/s00228-008-0515-5

Cited by 29 publications

(34 citation statements)

References 106 publications

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“…To our knowledge, there are no published studies reporting comprehensive oxysterol levels in the retina. 27HCh has been found in high levels in macrophage foam cells and atherosclerotic plaques ( 39,40 ), but its presence in the retina has not been previously reported. 24HCh was reported in the retina in one study ( 45 ), and this will be discussed in more detail below.…”

Section: Enzymatic Oxidationmentioning

confidence: 89%

“…Therefore, CYPs are probably not oxidizing cholesterol for the purpose of maintaining cholesterol homeostasis in the retina. They may play a minor supporting role in this regard, but their main function may be to generate small amounts of side-chain oxysterols for the purpose of gene regulation ( 40 ). Liver X receptors (LXRs) are known to be regulated by oxysterols ( 75,76 ) and are abundantly expressed in the retina (unpublished observations).…”

Section: Pharmacological Properties Of 7kchmentioning

confidence: 99%

“…27HCh is also found abundantly in atheromatous lesions ( 38 ). CYP27A1 may also be involved in cholesterol elimination in macrophages ( 39,40 ). The majority of the enzymatic B-ring hydroxylations of cholesterol take place in the liver by CYP7A1 and CYP3A4, which can oxidize cholesterol to form 7 ␣ -hydroxycholesterol (7 ␣ HCh) and 4 ␤ -hydroxycholesterol, respectively ( 32,39 ).…”

Section: Enzymatic Oxidationmentioning

confidence: 99%

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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: Enzymatic Oxidationmentioning

confidence: 89%

Section: Pharmacological Properties Of 7kchmentioning

confidence: 99%

Section: Enzymatic Oxidationmentioning

confidence: 99%

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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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“…Conversion of cholesterol into bile acids in the liver, together with the secretion of cholesterol into bile, is the major quantitative pathway for eliminating cholesterol from the body. 4 The initial stage of this process is catalyzed by the rate-limiting enzyme in the catabolism of cholesterol, cholesterol 7-hydroxylase (CYP7A1), 4 which is a cytochrome P-450 enzyme. In the study by Toshio et al, 5 the expression of CYP7A1 mRNA was decreased in spontaneously HT hyperlipidemic rats.…”

Section: Introductionmentioning

confidence: 99%

CYP7A1 genotypes and haplotypes associated with hypertension in an obese Han Chinese population

Zhao

et al. 2011

Hypertens Res

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This study investigated the association between single-nucleotide polymorphisms (SNPs; rs3808607 and rs1125226) within the CYP7A1 promoter and hypertension susceptibility in a Han Chinese population. From 2003 through 2006, a populationbased case-control study was performed in a cohort of 1187 randomly selected Han Chinese subjects. A sib-pair study for a transmission disequilibrium test analysis was carried out in 76 hypertensive (HT) families (n¼312) from northeastern Liaoning province. SNPs were detected using real-time PCR. No significant differences were found in the genotype or allele frequencies of either SNP (P40.05), with no excessive allele sharing. For rs3808607, the frequency of the AA genotype in obese hypertensive patients was 31.91%, significantly higher than in normotensive (NT) subjects (12.73%; odds ratio (OR)¼3.21, 95% confidence interval (CI)¼1.35-7.66). For rs3808607, the AA genotype frequency was significantly higher in obese male HT subjects (27.87%) than in matched NTs (7.41%; OR¼4.83, 95% CI¼1.03-22.65). After adjustment for environmental risk factors in obese participants, the AA genotype was associated with hypertension (OR¼3.395, 95% CI¼1. 412-8.162). Among subjects with body mass index X28 kg m À2 , the HT and NT groups had significantly different frequencies of Hap I (C/C) and Hap IV (A/A). The frequencies of rs3808607 alleles in the CYP7A1 gene differed significantly between obese HT and NT men. Haplotypes I and IV were associated with hypertension in obese participants.

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“…Whether other cholesterol transport proteins are involved in the movement of cholesterol to mitochondria is currently unknown. Unlike CYP7A1, which is expressed only in hepatocytes, mitochondrial CYP27A1 is expressed in many different tissues and cell types in the body and has been hypothesized to play a role in reverse cholesterol transport ( 35 ). CYP27A1 is a unique cytochrome P-450 enzyme in that it catalyzes the 27-hydroxylation of cholesterol as well as various bile acid biosynthetic intermediates ( 36 ).…”

mentioning

confidence: 99%

Bile acids as regulatory molecules

Hylemon

Zhou

Pandak

et al. 2009

Journal of Lipid Research

595

504

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Cytochrome P450 and gene activation—from pharmacology to cholesterol elimination and regression of atherosclerosis

Cited by 29 publications

References 106 publications

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

CYP7A1 genotypes and haplotypes associated with hypertension in an obese Han Chinese population

Bile acids as regulatory molecules

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