Interactions of MDL 29,311 and probucol metabolites with cholesteryl esters (original) (raw)
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The Journal of biological chemistry, 1992
The effect of 4,4'-(isopropylidenedithio)bis(2,6-di-t-butylphenol) (probucol) on cholesteryl ester physical state was examined in dry mixtures, phospholipid-containing dispersions, and cells. Probucol has little effect on the solid to isotropic transition of cholesteryl oleate, but broadens and decreases the enthalpy of the liquid-crystalline transitions at concentrations as low as 1-2 mol %. A probucol transition is only observed at concentrations greater than 20 mol %. The mesomorphic phases of the cholesteryl oleate/probucol mixtures were identified by visual inspection and polarized light microscopy. Mixtures are liquid at probucol concentrations in excess of 5 mol % at 37 degrees C. Probucol also dramatically reduces the enthalpy of the liquid-crystalline transitions of the cholesteryl oleate core of dispersions of the ester with phospholipids at a concentration of 10 mol %, reducing the enthalpy by greater than 80% and the transition temperatures by approximately 2 degrees...
The steatotic and cytotoxic effects of cholesterol oxides in cultured L cells
Food and Chemical Toxicology, 1984
Abstraet-Monolayers of L-cell cultures were incubated with oxygenated cholesterols and cellular protein was subsequently measured to assess the cytotoxicity of the cholesterol oxides. The site of oxidation of the cholesterol molecule was not reflected in the degree of cytotoxicity. Of the 12 cholesterol oxides tested, cholestan-3fl,5~,6fl-triol and cholestan-3,5-diene-7-one exhibited the greatest cytotoxicity, approximately 45% inhibition (reduction) in protein compared to the control at concentrations of 10/~ g/ml, after 1 day of incubation with the compounds. 5-Cholesten-3B,25-diol and 5-cholesten-3fl-ol-7-one were the most cytotoxic after 5 days' exposure with concentrations of 10pg/ml reducing the protein content to approximately 10% of the control. Lipid accumulation in the L cells (steatosis), as measured by Oil Red O-stainable droplets formed in response to cholesterol oxides was also investigated. Grade 3 steatosis (an increase in lipid droplets so that more than 75% of the L-cell cytoplasm was occupied by lipid droplets) after 1 day of exposure to cholesterol oxides generally reflected the cytotoxic effect of the same cholesterol oxides after 5 days' exposure. However some of the steatotic cholesterol oxides, such as the c~ and fl epimers of cholestan-5,6-epoxy-3fl-ol were highly active with respect to steatosis, increasing the grade 3 value to 209 and 390% of control, respectively, but were not cytotoxic. This has led to the suggestion that the cholesterol oxides have more than one mode of action in L cells.
Cholesterol oxidation: Health hazard and the role of antioxidants in prevention
Biological Research, 2003
BIOLOGICAL IMPORTANCE OF CHOLESTEROL Sterol cholesterol (cholest-5-en-ß-ol) is an essential metabolite required for major biological functions, such as the cell membrane structure where the steroid f o r m s , t o g e t h e r w i t h p h o s p h o l i p i d molecules, the integral part of the lipid b i l a y e r (S p e c t o r & Y o r e k , 1 9 8 5). Cholesterol is inserted into membrane bilayers with its long axis perpendicular to the plane of the membrane, preventing the crystallization of fatty acyl chains by fitting b e t w e e n t h e m (Y e a g l e , 1 9 8 5) a n d modifying the activity of membranebounded enzymes (Valencia et al., 1999). Cholesterol also provides the structural scaffolding for the synthesis of steroids a n d s t e r o i d h o r m o n e s , a n d f o r t h e biosynthesis of bile and bile acid salts. Sterol plays also an important role in embryonic development (Roux et al., 2000).
The Role of Cholesterol and Its Biosynthesis in Lymphocyte Proliferation and Differentiation
Annals of the New York Academy of Sciences, 1985
Most membranes of eucaryotes contain sterols with 27 to 30 carbon atoms. In mammalian cells the major membrane sterol is cholesterol (5-cholesten-3P-01). The physiochemical role of this molecule has been investigated intensively and is today fairly well understood, although some details still require further study. This subject has been reviewed and therefore we restrict ourselves to briefly summarizing the present state of knowledge on the role of membrane sterol in lymphocyte function.
Russian Journal of Bioorganic Chemistry, 2003
Incubation of 3 β-(2-hydroxy-2[ 3 H]-ethoxy)-5 α-cholest-8(14)-en-15-one with Hep G2 cells led to the accumulation of a radioactive polar product in the culture medium, which was identified as 3 β-(2-hydroxyethoxy)-15-keto-5 α-cholest-8(14)-ene-24-oic acid. Its structure was confirmed by a chemical counter synthesis. The labeled ketosterol was rapidly (t 1/2 = 6 min) and reversibly bound by Hep G2 cells. The intracellular concentration of 15-ketosterol decreased during incubation mainly due to the formation of a polar metabolite, secreted to the medium. The level of cholesterol biosynthesis was 22 ± 5% of the control value in Hep G2 cells at a 15-ketocholesterol concentration in the medium of 30 µ M. However, further incubation for 3 h in the medium without the ketosterol led to restoration of the level of biosynthesis to 85 ± 11% of the control value. These results suggest that inhibition of the cholesterol biosynthesis by 15-ketocholesterol in Hep G2 cells depends on the intracellular concentration of the inhibitor, which, in turn, is determined by the rate of its conversion into the polar metabolite.
Biochemical and Biophysical Research Communications, 2003
Atherosclerosis involves inflammatory processes, as well as cytotoxic and oxidative reactions. In atherosclerotic plaques, these phenomena are revealed by the presence of dead cells, oxidized lipids, and oxidative DNA damage, but the molecules triggering these events are still unknown. As 7b-hydroxycholesterol and 7-ketocholesterol, which are present at elevated concentrations in atherosclerotic lesions, are strongly cytotoxic and pro-oxidative, their effects were determined on cell death, superoxide anion and nitric oxide production, lipid peroxidation, and oxidative DNA damage. 7-Ketocholesterol-and 7b-hydroxycholesterol-induced cell death leads to a loss of mitochondrial potential, to increased permeability to propidium iodide, and to morphological nuclear changes (swelling, fragmentation, and/or condensation of nuclei). These effects are preceded by the formation of cytoplasmic monodansylcadaverine-positive structures and are associated with a rapid enhancement of cells overproducing superoxide anions, a decrease in cells producing nitric oxide, lipid peroxidation (formation of malondialdehyde and 4-hydroxynonenal adducts, low ratio of [unsaturated fatty acids]/[saturated fatty acids]) as well as oxidative DNA damage (8-oxoguanine formation). Noteworthy, none of the cytotoxic features previously observed with 7b-hydroxycholesterol and 7-ketocholesterol were noted with cholesterol, 7bhydroxycholesteryl-3-oleate and 7-ketocholesteryl-3-oleate, with the exception of a slight increase in superoxide anion production with 7b-hydroxycholesteryl-3-oleate. This finding supports the theory that 7b-hydroxycholesterol and 7-ketocholesterol could induce cytotoxic and oxidative processes observed in atherosclerotic lesions and that esterification of these compounds may contribute to reducing atherosclerosis progression.
Journal of Lipid Research, 1996
Oxysterols arising from the diet or through lipid peroxidation may be important in the modulation of cellular cholesterol metabolism. In this study, the metabolism of one of the oxysterols, 25-hydroxycholestero1(250HC), was examined in 5774 and mouse peritoneal macrophages. Uptake of 250HC from serum was rapid and substantial. Esterification of the cellular 250HC was also rapid as was hydrolysis of pre-formed esters. Like cholesterol, 250HC was removed from cells by an extracellular acceptor such as high density lipoprotein. Unlike cholesterol, 250HC was also rapidly and extensively removed from cells by serum albumin, but not by ovalbumin. The differential removal of oxysterols and cholesterol from cells by albumin allows separation of cellular effects due to oxysterols and cholesterol. In order to understand more about this differential efflux of sterols, a computer model for sterol mass transport in cells was used to compare intracellular trafficking of cholesterol and 250HC. The rate constants determined by this model for movement of sterols between cytoplasm and plasma membrane were similar for both cholesterol and 250HC, whereas those for esterification and ester hydrolysis as well as those for bidirectional movement between plasma membrane and extracellular medium were greater for 250HC than for cholesterol. I For both sterols, the rate-limiting step for removal of cellular esters appeared to be the rate of cytoplasmic ester hydrolysis. As 250HC and cholesterol differ significantly in aqueous solubility, the similarity in their rate constants for movement between cytoplasm and plasma membrane is consistent with facilitation of transport between these two loci.
Oxidation of liposomal cholesterol and its effect on phospholipid peroxidation
Chemistry and Physics of Lipids, 2007
Lipid peroxidation is believed to play an important role in the pathogenesis of many diseases. Much research has therefore been devoted to peroxidation of different lipids in biomembranes and in model systems (liposomes) of different compositions. Yet, in spite of the relative simplicity of the liposomes, the existing literature is insufficient to reach definite conclusions regarding basic questions including the susceptibility of cholesterol to oxidation, its effect on the peroxidation of polyunsaturated phospholipids such as palmitoyllinoleoylphosphatidylcholine (PLPC) and how cholesterol influences the effect of water-soluble antioxidants such as urate on the peroxidation.
Arteriosclerosis, thrombosis, and vascular biology, 2016
Oxidized products of probucol, spiroquinone and diphenoquinone, were shown to increase cell cholesterol release and plasma high-density lipoprotein (HDL) by inhibiting degradation of ATP-binding cassette transporter A1. We investigated whether these compounds enhance reverse cholesterol transport in mice. Spiroquinone and diphenoquinone increased ATP-binding cassette transporter A1 protein (2.8- and 2.6-fold, respectively, P<0.01) and apolipoprotein A-I-mediated cholesterol release (1.4- and 1.4-fold, P<0.01 and P<0.05, respectively) in RAW264.7 cells. However, diphenoquinone, but not spiroquinone, enhanced cholesterol efflux to HDL (+12%, P<0.05), whereas both increased ATP-binding cassette transporter G1 protein, by 1.8- and 1.6-fold, respectively. When given orally to mice, both compounds significantly increased plasma HDL-cholesterol, by 19% and 20%, respectively (P<0.05), accompanied by an increase in hepatic and macrophage ATP-binding cassette transporter A1 but...