Disease relevance of C00599

• Hepatic microsomes prepared from liver biopsy specimens obtained from a subject with cerebrotendinous xanthomatosis produced three times more 4-cholesten-3-one than the controls [1].
• The specificity and requirement of cholesterol as an HIV-1-associated lipid were investigated by replenishing cholesterol-deficient HIV-1 with cholesterol, cholestenone (a cholesterol structural analogue) or sphingomyelin (a structurally unrelated yet virion-associated lipid) [2].
• Of six steroids tested, cholesterol, cholest-4-en-3-one, cholest-4-en-3 beta-ol (allocholesterol), and androst-5-en-3 beta-ol-17-one supported growth of Eubacterium strain 403 [3].
• Cholesterol is oxidized by commercially available Pseudomonas fluorescens cholesterol oxidase to 6 beta-hydroperoxycholest-4-en-3-one as the initial product, with none of the expected produce, cholest-4-en-3-one, formed [4].
• Thin-layer chromatographic analysis showed the expression of the Streptomyces cholesterol oxidase gene resulting in the oxidation of cholesterol to 4-cholesten-3-one [5].

High impact information on C00599

• Here we show that Abeta:Cu2+ complexes oxidize cholesterol selectively at the C-3 hydroxyl group, catalytically producing 4-cholesten-3-one and therefore mimicking the activity of cholesterol oxidase, which is implicated in cardiovascular disease [6].
• Cell death induced by staurosporine or H2O2 did not elevate 4-cholesten-3-one levels [6].
• The increased production of cholestanol in cerebrotendinous xanthomatosis may be accounted for by enhanced hepatic formation of 4-cholesten-3-one [1].
• We report that introduction of cholest-4-en-3-one into caveolae membranes uncouples PDGFR autophosphorylation from tyrosine phosphorylation of neighboring proteins [7].
• Incubation of macrophages with LDL in the presence of increasing concentrations of cholestenone resulted in up to 52% enhanced lipoprotein cellular degradation suggesting that the cholestenone in CO-LDL might be involved in the enhanced cellular uptake of the modified lipoprotein.(ABSTRACT TRUNCATED AT 400 WORDS)[8]

Chemical compound and disease context of C00599

• While the buoyant density of cholesterol-defective HIV-1 can be restored by a cholesterol structural analogue, cholestenone, the requirement for cholesterol is essential for HIV-1 infectivity [2].
• One new anthraquinone, 1,8-dihydroxy-2-ethyl-3-methylanthraquinone (1), together with two known compounds octadecanoic acid (2) and cholest-4-en-3-one (3) was isolated from marine actinomycete Streptomyces sp. FX-58 [9].

Biological context of C00599

• Major biotransformation products included cholest-5-en-3-one, cholest-4-en-3-one, 26-hydroxycholest-4-en-3-one, androsta-1, 4-dien-3-17-dione, cholest-4-en-3-one-26-oic acid, chol-4-en-3-one-24-oic acid, pregn-4-en-3-one-20-carboxylic acid, and pregna-1, 4-dien-3-one-20-carboxylic acid [10].
• Crystalline cholest-4-en-3-one undergoes solid-state dimerization by UV radiation to give two ring A - ring A connected dimers [11].
• Ethisterone and 4-cholesten-3-one which cannot induce 11 beta-hydroxylase competed efficiently for plasma membrane binding sites; ethisterone, however also competed for cytosol binding sites and acted, in contrast with 4-cholesten-3-one, as antagonist in the induction of 11 beta-steroid hydroxylase in C. lunatus [12].
• The mutagenic activity of 4-cholesten-3-one and its major faecal by-products, 5beta-cholestan-3-one, was assessed in two in vitro assays, a bacterial mutation assay and an in vitro chromosome aberration assay [13].
• The results suggest that cholestenone is metabolized by two pathways, that is, the first hydroxylation occurs either at the C-20 position or at the C-22 position [14].

Anatomical context of C00599

• Upon oxidation of at least 70 % of the cholesterol in the plasma membrane to cholestenone, the phosphodiesterase activity in the plasma membrane approached that initiated by the disc membranes [15].
• Labeled cholesta-4,6-dien-3-one and 4-cholesten-3-one could be isolated from the intestinal contents 12 h after feeding [4-14C]7 alpha-hydroxy-4-cholesten-3-one to rabbits [16].
• [3H]Cholesterol-labeled mouse peritoneal macrophages incubated with acetyl-LDL, and both J774 and mouse peritoneal macrophages incubated with 25-hydroxy-cholesterol, also showed a shift of label from cholestenone to CE [17].
• Erythrocytes were treated briefly or continuously with cholesterol oxidase to convert a portion of the outer leaflet cholesterol to cholestenone, and the specific radioactivity of cholestenone was determined over the period of tracer equilibration [18].
• The results indicate the presence of a rat liver microsomal 6 beta-hydroxylase which can use 4-cholesten-3-one as a substrate and extend previous findings of similarities between soybean lipoxygenase and a nonspecific lipoxygenase in rat liver microsomes [19].

Associations of C00599 with other chemical compounds

• The very high activity of CYP27A1 towards the cholestanol precursor 4-cholesten-3-one may be of importance in connection with the accumulation of cholestanol in patients with CTX [20].
• A combination of spectroscopic (mass, nuclear magnetic resonance, ultraviolet, and infrared) and chromatographic (HPLC and GLC) methods showed that they are 5-alpha- cholestan-3-one (I) and cholest-4-en-3-one (II) [21].
• The transfer rate of cholest-4-en-3-one and epicholesterol between egg yolk phosphatidylcholine liposomes was much higher than that of cholesterol [22].
• When adipocytes were preincubated with the sterols before the addition of fisetin, cholestanone and cholestenone showed 74% and 66% inhibition of maximal methylation respectively [23].

Gene context of C00599

• Cholest-4-en-3-one appears to interfere with the normal interaction between PDGFR and its partners [7].
• Effect of 4-cholesten-3-one on lecithin-cholesterol acyltransferase activity and the lipid concentration in the serum of normocholesterolaemic and hypercholesterolaemic rats [24].
• Halo formation on the agar medium containing cholesterol depended on the conversion of cholesterol to 4-cholesten-3-one by the extracellular cholesterol oxidase [25].

Analytical, diagnostic and therapeutic context of C00599

• Isopycnic centrifugation of homogenates showed that the cholestenone had a peak buoyant density of 1.13 g/cm3 [26].
• Determination of natural cholestenone in rat adrenal extracts by high-performance liquid chromatography [27].
• However, 4-cholesten-3-one concentration remained very low (< 2 mg/g) and in line with values reported in the literature for subjects fed high or low fat diets [28].
• Male Wistar strain rats and PHHC (Prague hereditary hypercholesterolaemic) rats received an intraperitoneal injection of 4-cholesten-3-one for five days [24].

References