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PubMed1984

[Differential action of 7 beta-hydroxycholesterol on myocardial cells and fibroblasts. Obtaining primary cultures of pure myocardial cells].

Newborn rat myocardial cells, grown in primary cultures, beat synchronously. Addition of 7 beta-hydroxycholesterol, at a 2.5 microM concentration, impairs this synchrony and may even stop any contraction. The associated fibroblasts no longer adhere to the support, and can be washed away by fresh culture medium. This restores the synchronous beatings of the myocardial cells, the viability of which is then even improved while they grow in the absence of fibroblasts.

Animals↗
PubMed1981

Selective decrease of the viability and the sterol content of proliferating versus quiescent glioma cells exposed to 25-hydroxycholesterol.

The effects of 25-hydroxycholesterol (25-OHC), a potent inhibitor of sterol synthesis, on the growth, viability, and sterol content of C-6 rat glioma cells have been studied. Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and sterol synthesis in cells that were proliferating in medium supplemented with lipoprotein-poor fetal calf serum caused an arrest of growth after 24 hr. Prolonged incubation of serum-supplemented cells with 25-OHC resulted in a loss of morphological integrity and an 80% decline in cell viability, determined by trypan blue dye exclusion. In contrast, C-6 cells that were induced to enter a quiescent state by removal of serum from the medium remained viable and morphologically differentiated in the presence of 25-OHC. Following the addition of whole fetal calf serum to the medium, serum-free cells that had been incubated with 25-OHC for 3 days were able to resume proliferation. the selective killing of proliferating C-6 glioma cells by 25-OHC was correlated with a 45 to 50% decline in the sterol/phospholipid molar ratio, whereas the sterol/phospholipid ratio in the quiescent cells was not affected by 25-OHC. The results suggest that inhibitors of sterol synthesis may have potential as agents that might selectively decrease the growth and viability of glioma cells in the central nervous system without detriment to the normal nondividing neural cells.

Animals↗
PubMed1981

26-Hydroxycholesterol. Identification and quantitation in human serum.

Using isotope dilution mass spectrometry, 26-hydroxycholesterol was identified in the serum of normal adults. Total values ranged from 9.2 to 25.6 micrograms/100 ml of which 31-35% was free sterol. Density gradient ultracentrifugation indicates that the steroid is distributed among the low and high density lipoproteins.

Gas Chromatography-Mass Spectrometry↗
PubMed1994

Inhibitors of sterol synthesis. Tritium-labeled 26-hydroxycholesterol of high specific activity from a byproduct of the Clemmensen reduction of diosgenin.

(25R)-26-Hydroxycholesterol (I) was synthesized in six steps from (22Z,25R)-cholesta-5,22-diene-3 beta,26-diol (II) in 31% overall yield. The 26-tert-butyldiphenylsilyl ether of II was converted via its 3 beta-tosylate to (22Z,25R)-6 beta-methoxy-26-(tert- butyldiphenylsilyloxy)-3 alpha,5-cyclo-5 alpha-cholest-22-ene (V). Removal of the 26-silyl group of V gave (22Z,25R)-6 beta-methoxy-3 alpha,5-cyclo-5 alpha-cholest-22-en-26-ol, which was hydrogenated over platinum oxide and then hydrolyzed to I. Catalytic reduction in the presence of deuterium or tritium gas gave [2H]-I or [3H]-I, respectively. Analysis of the [2H]-I by mass spectrometry showed that all the deuterium was located in the sterol side chain, mainly as d2, d3, and d4 species. The 2H and 13C nuclear magnetic resonance (NMR) spectra of [2H]-I indicated that most of the deuterium was located at C-22 and C-23, with lesser amounts at C-24 and minor amounts at C-20, C-21, C-25, and C-27. NMR spectra of [2H]-I and its alpha-methoxy-alpha-(trifluoromethyl)phenylacetate diester showed no detectable 20S epimer and approximately 2% of the 25S epimer. The [3H]-I was prepared analogously to [2H]-I using carrier-free tritium and showed a specific activity of 16.9 Ci/mmol. All synthetic intermediates were characterized fully by 1H and 13C NMR, and representative 1H-1H coupling constants are given for the ring A protons of i-steroids.

Deuterium↗
PubMed1993

Modifying effect of 26-hydroxycholesterol on low-magnesium-induced atherosclerotic changes in the cultured human arterial smooth muscle cell.

This study investigated the modifying effect of 26-hydroxycholesterol (26-OHC) on low-Mg(2+)-induced atherosclerotic changes in human arterial smooth muscle cells. Cells were exposed to a medium containing a concentration of 142, 332, 665 and 949 microM Mg2+ (as control) for the designed periods. Half the cells were simultaneously exposed to 10 micrograms/ml of 26-OHC. The results showed that the cytotoxicity of low Mg2+ and the stimulating effect of low Mg2+ on cytosolic free Ca2+ level and 45Ca2+ uptake were accentuated by 26 microns OHC. The significant increase of [3H]thymidine incorporation by Mg2+ level at and lower than 332 was, however, counteracted by 26-OHC. While an increased [3H]leucine incorporation occurred only at a level of 665 microM Mg2+, an additional increase of [3H]leucine incorporation also occurred at a level of 142 microM Mg2+ in the presence of 26-OHC. We suggest that 26-OHC could modify the atherogenic effect of low Mg2+.

Arteriosclerosis↗
PubMed1996

Comparison of the intracellular metabolism and trafficking of 25-hydroxycholesterol and cholesterol in macrophages.

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-hydroxycholesterol (25OHC), was examined in J774 and mouse peritoneal macrophages. Uptake of 25OHC from serum was rapid and substantial. Esterification of the cellular 25OHC was also rapid as was hydrolysis of pre-formed esters. Like cholesterol, 25OHC was removed from cells by an extracellular acceptor such as high density lipoprotein. Unlike cholesterol, 25OHC 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 25OHC. The rate constants determined by this model for movement of sterols between cytoplasm and plasma membrane were similar for both cholesterol and 25OHC, whereas those for esterification and ester hydrolysis as well as those for bidirectional movement between plasma membrane and extracellular medium were greater for 25OHC than for cholesterol. For both sterols, the rate-limiting step for removal of cellular esters appeared to be the rate of cytoplasmic ester hydrolysis. As 25OHC 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.

Animals↗
PubMed1997

X-ray crystal structure of cytotoxic oxidized cholesterols: 7-ketocholesterol and 25-hydroxycholesterol.

The cytotoxic cholesterol derivative, 7-ketocholesterol, crystallizes in a monoclinic unit cell, space group P2(1) with a = 11.405 A, b = 6.288 A, c = 35.393 A and beta = 92.75 degrees (Z = 4). Its room temperature crystal structure was solved by direct methods, i.e., the minimal principle via the Shake-and-Bake (SnB) algorithm. In contrast to the continuous chain pattern found for the cholesterol monohydrate structure, hydrogen bonding in the 7-ketocholesterol structure is localized to specific sites via one water molecule that forms linkages between two O3 hydroxyl groups and one keto oxygen. The final weighted R factor for 4562 reflections was 0.144. The 25-hydroxycholesterol also crystallizes in a monoclinic unit cell (P2(1)), with a = 10.840 A, b = 14.533 A, c = 16.093 A and beta = 95.91 degrees (Z = 4). The low temperature structure was solved by DIRDIF. In this instance, molecular packing is anti-parallel in layers stabilized by hydrogen bonding networks via both hydroxyl functions, differing both from cholesterol monohydrate and the 7-ketocholesterol. The final weighted R-factor for 6566 reflections was 0.034. Functional differences of the oxysterols therefore, may be expressed by observed variations in the molecular packing and geometry.

Crystallization↗
PubMedDate not supplied

Cytotoxic properties of a phosphoglycoconjugated derivative of 7 beta-hydroxycholesterol upon normal and tumor cells in culture.

The cytotoxic activity of a new hydrosoluble axysterol derivative, a phosphoric acid diester of 7 beta-hydroxycholesterol (7 beta-OHC, one of the most toxic oxysterol) and of galactose has been evaluated using cultured tumor cells of various origins, and compared with 7 beta-OHC. As its parent compound, XG-142 exhibits a significant cytotoxic activity against all the cell lines tested, but the IC50's were higher than those obtained with 7 beta-OHC. Moreover, the cytotoxicity was slower to appear than after a 7 beta-OHC treatment. Cell phase distribution was analysed, and revealed some differences between the two compounds. Both oxysterols induced apoptosis at micromolar concentrations, as evidenced by several methods including agarose gel electrophoresis of fragmented DNA and flow cytometry of propidium iodide labeled cells. Apoptosis was also obtained when 7 beta-OHC and XG-142 were combined at concentrations unable to induce this type of cell death when used separately. Upon normal murine spleen cells, XG-142 was found to be less toxic than 7 beta-OHC, and the capacity to respond to Con A stimulation was preserved. Therefore, XG-142 can be considered as a promising soluble analogue of 7 beta-OHC, and its application as anticancer agent should be considered.

Animals↗
PubMed2004

Human and rodent type 1 11beta-hydroxysteroid dehydrogenases are 7beta-hydroxycholesterol dehydrogenases involved in oxysterol metabolism.

Interconversion between cortisone and the glucocorticoid receptor ligand cortisol is carried out by 11beta-hydroxysteroid dehydrogenase (11beta-HSD)isozymes and constitutes a medically important example of pre-receptor control of steroid hormones. The enzyme 11beta-HSD type 1 (11beta-HSD1) catalyzes the conversion of cortisone to its active receptor-binding derivative cortisol, whereas 11beta-HSD type 2 performs the reverse reaction. Specific inhibitors against the type 1 enzyme lower intracellular levels of glucocorticoid hormone, with an important clinical application in insulin resistance and other metabolic disorders. We report here on the in vitro oxysterol-metabolizing properties of human and rodent 11beta-HSD1. The enzyme, either as full-length, membrane-attached, or as a transmembrane domain-deleted, soluble form, mediates exclusively conversion between 7-ketocholesterol and 7beta-hydroxycholesterol with similar k(cat) values as observed with glucocorticoid hormones. Thus, human, rat, and mouse 11beta-HSD1 have dual enzyme activities like the recently described 7alpha-hydroxysteroid dehydrogenase/11beta-hydroxysteroid dehydrogenase from hamster liver, but differ fundamentally from the latter in that 7beta-OH rather than 7alpha-OH dehydrogenase constitutes the second activity. These results demonstrate an enzymatic origin of species differences in 7-oxysterol metabolism, establish the origin of endogenous 7beta-OH cholesterol in humans, and point to a possible involvement of 11beta-HSD1 in atherosclerosis.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2003

Comparison of the cytotoxic effects of beta-sitosterol oxides and a cholesterol oxide, 7beta-hydroxycholesterol, in cultured mammalian cells.

Phytosterols are plant sterols found in foods such as oils, nuts and vegetables. Phytosterols, in the same way as cholesterol, contain a double bond and are susceptible to oxidation. The objective of the present study was to assess the potential toxic effects of beta-sitosterol oxides on U937 cells. The effects of increasing concentrations (0-120 microm) of beta-sitosterol oxides on cellular cytotoxicity, apoptosis, antioxidant status and genotoxicity was assessed over 12, 24 and 48 h exposure periods. Following 12 h, the viability of cells treated with 120 microm-beta-sitosterol oxides was reduced to 51.7 % relative to control. At 24 and 48 h, both 60 and 120 microm-beta-sitosterol oxides caused a significant decrease in cell viability. For comparison, a decrease in viability of cells treated with a cholesterol oxide, 7beta-hydroxycholesterol (7beta-OH, 30 microm), was evident at 24 h. An increase in apoptotic cells, assessed using Hoechst 33342, indicates that the mode of cell death in U937 cells following exposure to 7beta-OH (30 microm) and beta-sitosterol oxides (60 and 120 microm) was by apoptosis. The increase in apoptotic cells after 12 h following treatment with 120 microm-beta-sitosterol oxides was accompanied by a decrease in cellular glutathione. Similarly, 7beta-OH (30 microm) treatment resulted in decreased glutathione at 12 h. Catalase activity was not affected by any of the treatments. beta-Sitosterol oxides had no genotoxic effects on U937 and V79 cells as assessed by the comet and sister chromatid exchange assays respectively. In general, the results indicate that thermally oxidised derivatives of beta-sitosterol demonstrate similar biological effects as 7beta-OH in U937 cells, but at higher concentrations.

Antioxidants↗
PubMed1982

Transformation of 25-Hydroxycholesterol by Rhizoctonia muneratii.

Rhizoctonia muneratii ATCC 13247 was capable of catalyzing the conversion of 25-hydroxycholesterol to the 3-oxo-4-ene. Hydroxylation at the 6alpha and 6beta positions with the concomitant 3-oxo-4-ene transformation was also observed. The addition of Triton X-100 to the growth medium immediately before steroid addition selectively prevented the appearance of the respective 6alpha-hydroxylated products. The observed conversions were indicative of the utility of microbial transformations in preparing hydroxylated steroids which can be useful for further synthetic modification or for study as pharmacological agents.

Journal Article↗
PubMed1976

Fragments formed by the side chain cleavage of a 20-aryl analog of 20alpha-hydroxycholesterol by adrenal mitochondria.

An analog of 20alpha-hydroxycholesterol, (20R)-20-phenyl-5-pregnene-3beta,20-diol, which is completely substituted at C-22 was prepared with radioisotopes at various positions. The analog labeled with 3H at C-M and 14C at C-4 and C-IU was converted into radioactive pregnenolone by an enzyme preparation derived from adrenal mitochondria. Cleavage of the phenyl analog labeled with 3H in the aromatic ring by the same enzyme preparation led to the formation of [3H]phenol. Using the substrate doubly labeled with 14C at C-4 and 3H in the aromatic ring, it appeared that the products of the reactions, pregnenolone and phenol, were formed in equal amounts. During incubation of the side chain labeled substrate, another labeled fragment was formed. It was identified as acetophenone, a product resulting from cleavage of the C17,20 bond. The steroidal fragment corresponding to this C8 ketone was traced using nuclear label analog. From its nonpolar chromatographic properties it appears to be a C-17-deoxy-C19 steroid.

Adrenal Medulla↗
PubMed1993

Cholesterol and 25-hydroxycholesterol retention in specimens of liver and aorta prepared for electron microscopy. II. Effect of filipin, osmium, digitonin and saponin.

Sprague-Dawley rats were injected intraperitoneally with [1 alpha, 2 alpha(n)-3H]cholesterol or 25-hydroxy-[26,27-3H]cholesterol, and one and five days later liver and aortic tissues were fixed. The extent to which these sterols were lost from the tissues during preparation for electron microscopy (EM) was examined utilizing different fixation procedures and various protective agents. Radioactive tracers, scintillation counting and standard EM techniques were used. Although most of the procedures examined caused major lipid losses, useful fixation procedures that allow retention of cholesterol or 25-hydroxy-cholesterol in liver and aortic tissues were found and are described here.

Animals↗