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At least 19 recordsLinked to original sources
PubMed1977

Bile acid synthesis in man. II. Determination of 7 alpha-hydroxycholesterol, (22R)-22-hydroxycholesterol, and 26-hydroxycholesterol in human meconium.

7 alpha-Hydroxycholesterol, (22R)-22-hydroxycholesterol and 26-hydroxycholesterol have been quantitated in human meconium. The method used tetrahydrofuran for extraction and solvolysis of the sulfate esters, liquid partition chromatography for the separation of the hydroxysterols, gas-liquid chromatography for quantitation, gas-liquid chromatography-mass spectrometry for identification, and tritiated and 14C-labeled tracers for overall recovery standards. (22R)-22-Hydroxycholesterol and 26-hydroxycholesterol were present almost entirely, ( greater than 93%) in the sulfate fraction at concentrations of 3.8-6.4 and 0.4-0.8 mg per 100 g meconium, respectively. Since free tritiated (22R)-22-hydroxycholesterol was used as the tracer to assess recovery of this hydroxysterol, the concentrations found for this compound may be minimal. Tritiated 26-hydroxycholesterol 3,26-disulfate was used as tracer to determine the levels of this compound, and the solvolysis procedure was optimized for recovery of 26-hydroxycholesterol and least decomposition of 7 alpha-hydroxycholesterol. No significant amounts of 7 alpha-hydroxycholesterol were found based on the tracer-free hydroxysterol as recovery standard.

Cholesterol↗
PubMed1972

Bile acid synthesis in man: metabolism of 7 -hydroxycholesterol- 14 C and 26-hydroxycholesterol- 3 H.

The pathways of bile acid synthesis in man were evaluated by studying the metabolism of 7alpha-hydroxycholesterol-4-(14)C and 26-hydroxycholesterol-16, 22-(3)H administered parenterally to individuals requiring external biliary drainage. Techniques for the identification of metabolites were thin-layer chromatography, column chromatography, gas-liquid chromatography with stream splitting, and crystallization to constant specific activity. It was found that both compounds were rapidly metabolized to bile acids and excreted in bile. Of the total radioactivity recovered in bile as bile acids, 87% of the 26-hydroxycholesterol-(3)H and 90% of the 7alpha-hydroxycholesterol-(14)C was found to be metabolized to both chenodeoxycholate and cholate. Compared to 7alpha-hydroxycholesterol, a greater proportion of 26-hydroxycholesterol was found to be metabolized to chenodeoxycholate. These findings indicate that both 7alpha-hydroxycholesterol and 26-hydroxycholesterol can be intermediates in the metabolism of cholesterol to bile acids in man. The observation that conversion to cholate takes place less readily after C-26 hydroxylation is consistent with previous findings in other species.

Autoradiography↗
PubMed1995

Effect of 25-hydroxycholesterol, 26-hydroxycholesterol and its analogue, 26-aminocholesterol, on protein content, protein synthesis and LDH leakage in mouse epidermal cells.

The cytotoxicity of 25-hydroxycholesterol, 26-hydroxycholesterol and its analogue, 26-aminocholesterol was investigated in murine epidermal cell line, HEL-30. Lactate dehydrogenase (LDH) leakage, protein synthesis and protein content were determined after exposure of cell monolayers to the compounds ranging from 0.1-200 microM for 2, 6, or 24 h. 26-Aminocholesterol affected all the parameters studied time and concentration dependently; 25-hydroxycholesterol and 26-hydroxycholesterol were not toxic for HEL-30 cells. The cellular target for 26-aminocholesterol was primarily the membrane, since the LDH leakage was already detectable 10 min after exposure. On the other hand, for the other two oxysterols a protective role on this structure might be postulated. In fact 25-hydroxycholesterol and 26-hydroxycholesterol decreased the natural LDH leakage due to the ageing of the culture. In addition, 20 microM 25-hydroxycholesterol reversed the effect of moderately lytic doses of 26-aminocholesterol and Triton X-100, but not of sodium dodecyl sulfate.

Analysis of Variance↗
PubMed1995

Low density lipoprotein (LDL) cholesterol is converted to 27-hydroxycholesterol in human fibroblasts. Evidence that 27-hydroxycholesterol can be an important intracellular mediator between LDL and the suppression of cholesterol production.

The formation of oxysterols in cultured human fibroblasts and their physiological roles as intracellular regulators of cholesterol production have been investigated. In the presence of low density lipoproteins (LDL) normal fibroblasts converted LDL cholesterol to the oxysterol 27-hydroxycholesterol in quantities apparently sufficient to down-regulate 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The production of 27-hydroxycholesterol started 3-8 h after the addition of LDL to the incubation medium, and during this time the activity of HMG-CoA reductase decreased by 73%. Formation of other biologically active oxysterols such as 7 alpha-hydroxycholesterol, 24-hydroxycholesterol, and 25-hydroxycholesterol was not observed. When 27-hydroxylation of LDL cholesterol in mitochondria was selectively prevented by treating normal fibroblasts with cyclosporin A or by using fibroblasts genetically lacking sterol 27-hydroxylase, the suppressive effect of LDL on HMG-CoA reductase was reduced by a factor of about 10. In the absence of LDL or when the fibroblasts lacked LDL-receptors, the cells did not produce detectable amounts of 27-hydroxycholesterol, and HMG-CoA reductase was up-regulated. The results provide strong evidence that 27-hydroxycholesterol is an important intracellular mediator between LDL and the suppression of HMG-CoA reductase in human fibroblasts. The mitochondrial uptake/metabolism of LDL cholesterol seems to be a biologically important extension of the LDL pathway in human cells, since the mitochondrial products of LDL cholesterol may regulate cholesterol homeostasis or be precursors of steroid hormones or bile acids. This pathway, which has now been demonstrated in fibroblasts, may link together the two 22-year-old observations that LDL as well as oxysterols can down-regulate HMG-CoA reductase in cells.

Carbon Radioisotopes↗
PubMed1997

7alpha-Hydroxylation and 3-dehydrogenation abolish the ability of 25-hydroxycholesterol and 27-hydroxycholesterol to induce apoptosis in thymocytes.

Oxygenated derivatives of sterols (oxysterols), including 25-hydroxycholesterol and 27-hydroxycholesterol, have immunosuppressive effects. Oxysterols can directly induce apoptosis in immature thymocytes, cells which are inherently sensitive to induction of programmed cell death. For that reason, the metabolism of 25-hydroxycholesterol and 27-hydroxycholesterol in mouse thymus has been studied. When incubated with thymic tissue, both oxysterols were found to be 7alpha-hydroxylated with subsequent oxidation to 7alpha-hydroxy-3-oxo-delta4 steroids. A minor fraction of 27-hydroxycholesterol was also metabolised to 3beta-hydroxy-5-cholestenoic, 3beta,7alpha-dihydroxy-5-cholestenoic and 7alpha-hydroxy-3-oxo-4-cholestenoic acids. The 7alpha-hydroxylase was found to be localised to the thymic epithelial cells and the reaction was stimulated by interleukin-1beta and inhibited by metyrapone and RU486. In contrast to 25-hydroxycholesterol and 27-hydroxycholesterol, the 7alpha-hydroxylated metabolites, 7alpha,25-dihydroxycholesterol, 7alpha,25-dihydroxy-4-cholesten-3-one and 7alpha,27-dihydroxy-4-cholesten-3-one did not induce thymocyte apoptosis. The results suggest that 7alpha-hydroxylation may be of regulatory importance, possibly by protecting the developing thymocytes against toxic effects by oxysterols.

Animals↗
PubMedDate not supplied

Bile acid metabolism in cirrhosis. VIII. Quantitative evaluation of bile acid synthesis from [7 beta-3H]7 alpha-hydroxycholesterol and [G-3H]26-hydroxycholesterol.

In order to evaluate more definitively the observed aberrations in the synthesis of cholic and chenodeoxycholic acids in patients with advanced cirrhosis, two bile acid biosynthesis pathways were examined by determining the efficiency of conversion of [3H]7 alpha-hydroxycholesterol and [3H] 26-hydroxycholesterol to primary bile acids. Bile acid kinetics were determined by administration of [14C]cholic and [14C]chenodeoxycholic acids. Cholic acid synthesis in cirrhotic patients was markedly depressed (170 vs. 927 mumoles per day)( while chenodeoxycholic acid synthesis was reduced to a much lesser degree (227 vs. 550 mumoles per day). The administration of [3H]7 alpha-hydroxycholesterol allowed for an evaluation of the major pathway of bile acid synthesis via the 7 alpha-hydroxylation of cholesterol. This compound was efficiently incorporated into primary bile acids by the two normal subjects (88 and 100%) and two cirrhotic patients (77 and 91%). However, the recovery of the label in cholic acid was slightly less in cirrhotic patients than in normal subjects. [3H]26-hydroxycholesterol was administered to ascertain the contribution of the 26-hydroxylation pathway to bile acid synthesis. All study subjects showed poor conversion (9 to 22%) of this intermediate into bile acids. The results of this study suggest that a major block in the bile acid synthesis pathway in cirrhosis is at the level of 7 alpha-hydroxylation of cholesterol (impairment of 7 alpha-hydroxylase) and /or in the feedback triggering mechanism regulating bile acid synthesis. The data also suggest that the 26-hydroxylation pathway in normal subjects and patients with cirrhosis is a minor contributor to synthesis of the primary bile acids. Therefore, the relative sparing of chenodeoxycholic acid synthesis observed in cirrhotic patients is not due to preferential synthesis of this bile acid via the 26-hydroxylation pathway.

Adult↗
PubMed1995

7 alpha-Hydroxylation of 25-hydroxycholesterol and 27-hydroxycholesterol in human fibroblasts.

The metabolism of 27-hydroxycholesterol and 25-hydroxycholesterol was studied in cultures of human diploid fibroblasts. Both steroids underwent 7 alpha-hydroxylation with subsequent oxidation to 7 alpha-hydroxy-3-oxo-delta 4 steroids. A minor fraction of the 27-hydroxysteroids was oxidized to acids. Competition experiments indicated that both hydroxycholesterols were hydroxylated by the same enzyme, different from cholesterol 7 alpha-hydroxylase. 7 alpha,25-Dihydroxycholesterol suppressed the activity of HMG-CoA reductase at least as effectively as 25-hydroxycholesterol whereas 7 alpha,25-dihydroxy-4-cholesten-3-one was a less effective suppressor. The results suggest that cholesterol might be converted to 7 alpha-hydroxylated bile acid precursors in extrahepatic tissues in vivo and that the regulation of the activity of HMG-CoA reductase by oxysterols might be modulated by 7 alpha-hydroxylation and subsequent oxidation by 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase.

Cells, Cultured↗
PubMed1996

Formation of cholic acid and chenodeoxycholic acid from 7 alpha-hydroxycholesterol and 27-hydroxycholesterol by primary cultures of human hepatocytes.

It has been suggested that chenodeoxycholic acid is preferentially formed by the alternative or 'acidic' pathway of bile acid biosynthesis starting with 27-hydroxylation of cholesterol, while cholic acid is derived from 7 alpha-hydroxycholesterol which initiates the 'neutral' pathway. We have studied bile acid formation from each of these precursors using human hepatocytes cultured in a novel sandwich collagen configuration. Culture supernatants were analyzed using capillary gas chromatography and gas chromatography-mass spectrometry. 27-Hydroxycholesterol and 7 alpha-hydroxycholesterol were both found to be efficiently converted to cholic acid as well as chenodeoxycholic acid. Analysis of acidic intermediates after addition of 7 alpha-hydroxycholesterol to the cultures revealed a significant increase of side-chain oxygenated C24- and C27-steroids with a 3-oxo-7 alpha-hydroxy-delta 4-ring structure. These data indicate that (i) the 'neutral' pathway is connected to the 'acidic' pathway by side-chain oxidation of C27-steroids with a 3-oxo-7 alpha-hydroxy-delta 4-ring structure and that (ii) the relative formation of cholic acid and chenodeoxycholic acid is regulated by metabolic events distal to the initial hydroxylation at either position 7 or position 27 of the cholesterol molecule.

Adult↗
PubMed1994

Antiproliferative and teratogenic activities of the bishemisuccinates of 7 alpha-hydroxycholesterol and 7 beta-hydroxycholesterol.

1. The bishemisuccinates of 7 alpha-hydroxycholesterol and 7 beta-hydroxycholesterol induced a dose-dependent decrease in the incorporation of [3H]thymidine into fibroblast cell line (3T3), macrophage-like cell line (P388D1) and rat hepatoma cell line (H35). Concomitantly there was a reduction in cell viability. 2. The 3T3 cells were less susceptible than P388D1 and H35 cells. 3. The aforementioned derivatives of 7 alpha-hydroxycholesterol and 7 beta-hydroxycholesterol produced malformations in cultured embryos including abnormalities in yolk sac circulation, heartbeat, body axis, otic vesicle, branchial apparatus, cranial neural tube and forelimb bud. Axial length and somite number were reduced.

3T3 Cells↗
PubMed1979

Sterol synthesis in variant Chinese hamster lung cells selected for resistance to 25-hydroxycholesterol. Cross-resistance to 7-ketocholesterol, 20alpha-hydroxycholesterol, and serum.

Two lines of Chinese hamster lung (Dede) cells which are resistant to the killing effect of 25-hydroxycholesterol, and which grow to confluence in its presence, have been isolated. One of the resistant lines exhibited a high to normal growth rate and normal levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34) activity and sterol synthesis in the presence of concentrations of 25-hydroxycholesterol that caused nearly complete suppression of these functions in wild type cells. The other variant line showed partial resistance to the inhibitory effects of the diol upon cell growth, sterol synthesis, and HMG-CoA reductase activity. The resistant phenotypes remained stable when the cells were maintained in the absence of the selecting agent. The Km (HMG-CoA), thermal stability, and susceptibility to inhibition by Mg2+ and ATP of HMG-CoA reductase were unaltered in both of the resistant lines. The two lines selected for growth in the presence of 25-hydroxycholesterol were also resistant to the inhibitory effects of 7-ketocholesterol, 20alpha-hydroxycholesterol, and serum upon HMG-CoA reductase and sterol synthesis, suggesting that suppression of cholesterol synthesis by these inhibitors involves a common step.

Biological Transport↗
PubMed1982

Complementary recessive 25-hydroxycholesterol-resistant somatic cell mutants--assay of 25-hydroxycholesterol binding activity.

Complementation analysis of recessive 25-hydroxycholesterol-resistant mutants of the CHO-Kl cell shows the existence of at least two complementation groups, one of which is missing a binding activity for 25-hydroxycholesterol. Both complementation groups are shown to be refractory to inhibition of cellular HMG-CoA reductase activity and in the inhibition of biosynthesis of this enzyme by 25-hydroxycholesterol.

Animals↗
PubMed1995

Effects of 26-aminocholesterol, 27-hydroxycholesterol, and 25-hydroxycholesterol on proliferation and cholesterol homeostasis in arterial myocytes.

The major relation existing between cell growth and cholesterol homeostasis prompted us to investigate the effect of 26-aminocholesterol (26-NH2), 27-hydroxycholesterol (27-OH), and 25-hydroxycholesterol (25-OH) on these cellular events. To test this relation, we incubated human and rat arterial myocytes with the sterols for 72 hours. All the tested compounds (0.5 to 7.5 mumol/L) inhibited rat and human myocyte proliferation and cholesterol biosynthesis in a dose-dependent manner. 26-NH2 was more potent than oxysterols in inhibiting human myocyte proliferation but equieffective in rat cells; 27-OH and 25-OH displayed similar activity in both cell lines. Inhibition of nuclear incorporation of thymidine in rat myocytes is consistent with decreased cell count. The antiproliferative effect of the tested sterols was reversible. The high inhibition (80%) of cholesterol biosynthesis necessary to induce a decrease in myocyte proliferation suggests a causal relation between the cholesterol synthetic pathway and these cellular processes. In addition, all the tested sterols were able to inhibit hydroxymethyl glutaryl-coenzyme A reductase activity in intact myocytes but not in cell-free extracts. The finding that 26-NH2 but not 27-OH or 25-OH does not suppress LDL receptor activity in either human or rat myocytes supports the achievement of selectivity over the coordinately regulated LDL receptor gene. The ability of 26-NH2 to interfere with myocyte proliferation and cholesterol synthesis without affecting the LDL receptor pathway confers at least in vitro a pharmacological interest on the compound in the process of atherogenesis.

Animals↗
PubMed1975

Mass spectrometric study of the enzymatic conversion of cholesterol to (22R)-22-hydroxycholesterol, (20R,22R)-20,22-dihydroxycholesterol, and pregnenolone, and of (22R)-22-hydroxycholesterol to the lgycol and pregnenolone in bovine adrenocortical preparations. Mode of oxygen incorporation.

Incubation of cholesterol with a bovine adrenocortical mitochondrial acetone-dried powder preparation yielded (22R)-22-hydroxycholesterol (I), (20R,22R)-20,22-dihydroxycholesterol(II), and pregnenolone (III) which were conclusively identified by combined gas chromatography-mass spectrometry. Incubations with [4-14C]cholesterol yielded I, II, and III with specific activities (determined from partial mass-spectral scans) not significantly different from those of the used substrate or the cholesterol reisolated after the incubation, demonstrating that the isolated compounds arose mostly, if not entirely, from the substrate cholesterol. Incubations in an 18O-enriched atmosphere yielded I, II, and III with 18O at position C-22, C-20 and C-22, and C-20, respectively, providing evidence that the hydroxyl groups of the side chain of I and II and the C-20 oxygen atom of III originated from molecular oxygen. The distribution of the oxygen atoms in II after incubation with 18O2 and 16O2 (devoid of 16O18O) proved that the hydroxyl groups of the side chain of II were introduced from two different molecules of oxygen, consistent with a sequential hydroxylation of cholesterol. No (20S)-20-hydroxycholesterol was found. Incubation of I in an 18O-enriched atmosphere afforded II and III with 18O at C-20.

Adrenal Cortex↗
PubMed1989

Hydroxycholesterols in serum from hypercholesterolaemic patients with and without bile acid sequestrant therapy.

To assess the effect of bile acid sequestrant therapy on bile acid precursors in plasma, we determined hydroxycholesterols in serum from patients with primary hypercholesterolaemia. Compared with a group of 5 male and 12 female patients without any lipid-lowering drug therapy, which has normal to slightly elevated 7 alpha-hydroxycholesterol, normal 7 beta-hydroxycholesterol and high normal to elevated 26-hydroxycholesterol levels, a group of 5 male and 9 female patients, using colestipol had higher 7 alpha-hydroxycholesterol without overlap, and higher 7 beta-hydroxycholesterol levels, but similar levels of 26-hydroxycholesterol. In the latter group, the ratio between 7 alpha-hydroxycholesterol and total cholesterol in serum was also higher without overlap. Both groups did not differ for age, body weight, body mass index and serum lipid levels. In the group of patients without lipid-lowering drug therapy, 7 alpha-hydroxycholesterol correlated positively with total and low-densitylipoprotein cholesterol, 7 beta-hydroxycholesterol negatively with body weight and body mass index, and 26-hydroxycholesterol positively with body weight. In both groups, 7 alpha-hydroxycholesterol correlated positively with 7 beta-hydroxycholesterol. These results suggest that (1) bile acid sequestrants enhance bile acid synthesis via the 7 alpha-hydroxylation but not via the 26-hydroxylation pathway, (2) serum 7 alpha-hydroxycholesterol level and the ratio between this hydroxycholesterol and total cholesterol in serum might be suitable parameters to check intake of bile acid sequestrants irrespective of dose, and (3) 7 beta-hydroxycholesterol is unlikely to be the result of cholesterol auto-oxidation in vitro.

Adult↗
PubMed2001

From brain to bile. Evidence that conjugation and omega-hydroxylation are important for elimination of 24S-hydroxycholesterol (cerebrosterol) in humans.

The brain is the almost exclusive site of formation of 24S-hydroxycholesterol in man, and there is a continuous flux of this oxysterol across the blood-brain barrier into the circulation. The hepatic metabolism of 24S-hydroxycholesterol was studied here by three different approaches: incubation of tritium-labeled 24S-hydroxycholesterol with human primary hepatocytes, administration of tritium-labeled 24S-hydroxycholesterol to a human volunteer, and quantitation of free and conjugated 24S-hydroxycholesterol and its neutral metabolites in ileocecal fluid from patients with ileal fistulae. 24S-Hydroxycholesterol as well as 24R-hydroxycholesterol were converted into bile acids by human hepatocytes at a rate of about 40% of that of the normal intermediate in bile acid synthesis, 7 alpha-hydroxycholesterol. There was also a conversion of 24S-hydroxycholesterol into conjugate(s) of 5-cholestene-3 beta,24S,27-triol at a rate similar to the that of conversion into bile acids. When administered to a human volunteer, labeled 24S-hydroxycholesterol was converted into bile acids at about half the rate of simultaneously administered labeled 7 alpha-hydroxycholesterol. Free, sulfated, and glucuronidated 24S-hydroxycholesterol and 5-cholestene-3 beta,24,27-triol were identified in ileocecal fluid. The excretion of these steroids was about 3.5 mg/24 h, amounting to more than 50% of the total estimated flux of 24S-hydroxycholesterol from the brain. It is concluded that 24S-hydroxycholesterol is a less efficient precursor to bile acids and that about half of it is conjugated and eliminated in bile as such or as a conjugate of a 27-hydroxylated metabolite. The less efficient metabolism of 24S-hydroxycholesterol may explain the surprisingly high levels of this oxysterol in the circulation and is of interest in relation to the suggested role of 24S-hydroxycholesterol as a regulator of cholesterol homeostasis.

Bile↗
PubMed1983

Regulation of acyl CoA:cholesterol acyltransferase by 25-hydroxycholesterol in rabbit intestinal microsomes and absorptive cells.

The regulation of rabbit intestinal acyl CoA:cholesterol acyltransferase (ACAT) by 25-hydroxycholesterol was studied. 25-Hydroxycholesterol significantly increased jejunal microsomal ACAT activity. The stimulation of ACAT activity by 25-hydroxycholesterol was inversely related to microsomal cholesterol content. In enterocytes, 25-hydroxycholesterol stimulated cholesteryl ester synthesis 6-fold. The esterification of cholesterol, taken up by enterocytes from liposomes or bile salt micelles, was increased by 25-hydroxycholesterol. This, however, did not affect the rate of uptake of cholesterol by the cells. In intestinal cells from rabbits fed cholesterol, the effect of 25-hydroxycholesterol on cholesteryl ester synthesis was 50% of that in cells prepared from animals fed no cholesterol. 25-Hydroxycholesterol stimulated the esterification of newly synthesized cholesterol. As new free cholesterol increased in enterocytes, 25-hydroxycholesterol lost its effect. Despite large amounts of newly synthesized cholesterol, oleic acid incorporation into cholesteryl ester was not increased. We conclude that 25-hydroxycholesterol increases intestinal ACAT activity. The effect of 25-hydroxycholesterol on ACAT is dependent upon the availability of cholesterol to the enzyme. At cholesterol concentrations below saturation, the oxygenated sterol has a stimulatory effect. If ACAT is saturated, 25-hydroxycholesterol has no effect. ACAT catalyzes the esterification of two separate pools of cholesterol within the enterocyte, i.e., newly synthesized cholesterol and membrane cholesterol. 25-Hydroxycholesterol increases the esterification rate of cholesterol in both pools.

Acyltransferases↗