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Biomedical subjects

G Salen

Publications and source records attributed to G Salen.

At least 199 records · Page 11Linked to original sources
PubMed1982

Identification of 5 alpha-stanols in patients with sitosterolemia and xanthomatosis: stereochemistry of the protonolysis of steroidal organoboranes.

Plasma and fecal sterols of patients who exhibited tendon xanthomas with normal plasma cholesterol levels were studied. Plasma levels were (mg/dl mean +/- SD): cholesterol 232 +/- 36; cholestanol 5.9 +/- 2.1 (normal less than 0.6); sitosterol 18 +/- 5.6 (normal less than 1.0); campesterol 11 +/- 3.3 (normal less than 1.0). Other sterols such as sitostanol and campestanol (the 5 alpha-dihydro derivatives of sitosterol and campesterol) were also present in large amounts. Examination of the feces from these subjects showed cholesterol, sitosterol, campesterol and their 5 beta-saturated derivatives. Presence of 5 alpha-stanols in the plasma, and their absence in the feces indicates that the 5 alpha-stanols are synthesized endogenously within the body rather than in the intestine by colonic bacteria. The absolute identification of the structures of these 5 alpha-stanols was elucidated via hydroboration of their corresponding unsaturated sterols coupled with protonolysis of the resultant organoboranes.

Boranes↗
PubMed1982

Improved synthesis of 3 alpha, 7 alpha, 12 alpha, 24 = xi-tetrahydroxy-5 beta-cholestan-26-oic acid.

This paper describes three simple and short methods for the conversion of cholic acid into cholylaldehyde with protected hydroxyl groups. The first method involves lithium aluminum hydride reduction of the tetrahydropyranyl ether of methyl cholate and oxidation of the resulting primary alcohol with pyridinium chlorochromate. The second method employs diborane for the reduction of the -COOH group to the -CH2OH group, while the third method involves the reduction of 3 alpha, 7 alpha, 12 alpha-triformyloxy-5 beta-cholan-24-oic acid (as the acid chloride) directly into 3 alpha, 7 alpha, 12 alpha-triformyloxy-5 beta-cholan-24-al with TMA-ferride (tetramethylammonium hydridoirontetracarbonyl). The aldehyde obtained by any of the above methods underwent smooth Reformatsky reaction with ethyl alpha-bromopropionate to yield 3 alpha, 7 alpha, 12 alpha, 24 xi-tetrahydroxy-5 beta-cholestan-26-oic acid.

Cholestanols↗
PubMed1982

Ursodeoxycholic acid: a safe and effective agent for dissolving cholesterol gallstones.

Ursodeoxycholic acid, 250 to 300, 500 to 600, or 900 to 1000 mg/d, was given orally for 6 to 38 months to 53 patients with cholesterol gallstones and functioning gallbladders. Forty-two patients had greater than 50% reduction in gallstone volume, number, or both, without apparent dose dependence and 27 of these patients had complete gallstone dissolution. Results of laboratory studies including liver function tests were not affected adversely and biliary lithocholic acid concentration did not increase during therapy. Most biliary symptoms seemed to disappear within 3 months and no patient developed diarrhea. Large diameter and increased number of gallstones were found to hinder dissolution. The percentage of biliary ursodeoxycholic acid increased with increasing dose and reached a maximum of 50% to 60% of total bile acids at a dose of about 10 to 12 mg/kg body weight. d. Biliary lithogenic index was reduced significantly during treatment with ursodeoxycholic acid, 500 to 600 and 900 to 1000 mg/d. Thus, ursodeoxycholic acid appears to be a safe and effective alternative to surgery in selected patients with gallstones.

Bile Acids and Salts↗
PubMed1982

Effect of 7-ketolithocholic acid on bile acid metabolism in humans.

The effect of 7-ketolithocholic acid on biliary bile acid composition, cholesterol saturation, and as an intermediate in the conversion of chenodeoxycholic acid to ursodeoxycholic acid was investigated in 5 subjects with gallstones. After 7-ketolithocholic acid (400 mg/day) was administered orally for 14 days, biliary bile acid composition changed: The proportion of cholic acid decreased (from 45% to 19%), deoxycholic acid decreased (from 15% to 10%), chenodeoxycholic acid increased markedly (from 36% to 59%), ursodeoxycholic acid increased (from 36% to 59%), ursodeoxycholic acid increased (from 2% to 7%), and lithocholic acid increased (from 2% to 5%), while only trace amounts of 7-ketolithocholic acid were detected. During this treatment, the biliary lithogenic index fell from 2.6 to 0.9 and was accompanied by a pronounced drop in biliary cholesterol concentration. After biliary bile acid levels became constant [24-14C]chenodeoxycholic acid was given intravenously as a pulse-label, and the resultant biliary ursodeoxycholic acid and lithocholic acid specific activity curves showed a precursor--product relationship with chenodeoxycholic acid. Similarly, when uniformly labeled 7-[24-14C]ketolithocholic acid was fed (400 mg/day, 1000 +/- 100 dpm/mg) the specific activities of biliary chenodeoxycholic acid and ursodeoxycholic acid became constant and approximated each other, but these were only 75% as high as the fed 7-ketolithocholic acid. These results indicate that 7-ketolithocholic acid is absorbed, and suppresses endogenous bile acid production and biliary cholesterol secretion. Both isotopic experiments infer that ursodeoxycholic acid and lithocholic acid are formed from chenodeoxycholic acid and not from 7-ketolithocholic acid. The reduction in biliary lithogenic index and in cholesterol concentration suggest that low doses of 7-ketolithocholic acid may be effective in dissolving gallstones.

Bile↗
PubMed1982

Biosynthesis of cholesterol, lanosterol, and delta 7-cholestenol, but not cholestanol, in cultured fibroblasts from normal individuals and patients with cerebrotendinous xanthomatosis.

The cholesterol and cholestanol biosynthetic pathways and the control of cholesterolgenesis were investigated in skin fibroblasts, from patients with cerebrotendinous xanthomatosis (CTX) and from normal subjects, growth in a lipoprotein deficient (d less than 1.25 g/ml) medium. [3H]Acetate was added to the culture medium and its incorporation into sterols was assayed by both argentation and reversed-phase thin-layer chromatography (TLC). The labeling patterns were similar in both CTX and control cells with 3H being found, in order of increasing activity, in lanosterol, delta 7-cholestenol, and cholesterol. No 3H-labeled material at all, however, could be detected in the TLC mobility region corresponding to cholestanol. The ratio of cholestanol to cholesterol in the low density lipoprotein (LDL) subfraction from the plasma of individuals with CTX ranged from 1.4 to 5.3%, which is equal to or slightly greater than the ratio in whole plasma. Approximately 65-70% of the total plasma and LDL cholestanol and cholesterol were esterified. Since CTX-LDL, added to incubates of normal cells and normal LDL added to CTX fibroblasts suppressed HMG-CoA reductase activity and stimulated cholesterol esterification equally, and since 125-I-labeled control LDL was degraded with normal kinetics from the surface of CTX fibroblasts, both CTX-LDL and CTX fibroblasts LDL membrane receptors appear to be biologically normal. These results suggest that 1) cholesterol is synthesized in cultured CTX and control fibroblasts via delta 7-cholestenol, a C-24,25 saturated intermediate; 2) cholestanol is not synthesized in the skin of CTX patients but is transported there from the liver via the plasma LDL; and 3) CTX is not a disease associated with a defect of peripheral tissue LDL receptors.

Brain Diseases, Metabolic↗
PubMed1981

A unique patient with coexisting cerebrotendinous xanthomatosis and beta-sitosterolemia.

An adult Chinese man presented with tendinous and tuberous xanthomatosis and severe atheromatous changes in the coronary arteries. In addition, he had chronic hemolytic anemia, with spherostomatocytic erythrocytes. Cerebrotendinous xanthomatosis was diagnosed on the basis of increased cholestanol levels in his plasma, red cells and xanthoma, changes in bile acid composition due to the defective synthesis of chenodeoxycholic acid. Coexisting beta-sitosterolemia was confirmed by the finding of large amounts of the plant sterols such as beta-sitosterol and campesterol. This is the first report of these two rare lipid storage disorders in the same patient.

Adult↗
PubMed1981

Synthesis of biological precursors of cholic acid II.

This paper describes the partial syntheses of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-al, 7 alpha, 12 alpha, 26-trihydroxy-5 beta-cholestan-3-one and 7 alpha, 12 alpha-dihydroxy-3-oxo-5 beta-cholestan-26-al via Ag2CO3/Celite oxidation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 26-tetrol. These bile alcohols were resolved by analytical and preparative TLC, characterized by gas-liquid chromatography and mass spectrometry. These compounds will be useful to delineate further the mechanism of oxidation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol on the pathway to cholic acid.

Cholestanols↗
PubMed1981

p-Toluenesulfonic acid/methanol: mild reagent for the preparation of bile acid methyl esters.

An improved method for the preparation of bile acid methyl esters is described. This is achieved by the addition of catalytic amounts of p-toluenesulfonic acid in a solution of bile acid in methanol. Advantages of this procedure over conventional methods include (1) use of a mild solid acid catalyst which prevents the formation of undesirable byproducts, (2) isolation of a solid product of high purity and (3) utilization of a relatively safe reagent in comparison to other methods involving diazomethane, hydrochloric acid or sulfuric acid.

Benzenesulfonates↗
PubMed1981

Abnormal high density lipoproteins in cerebrotendinous xanthomatosis.

The plasma lipoprotein profiles and high density lipoproteins (HDL) were characterized in patients with the genetic disease cerebrotendinous xanthomatosis (CTX). Abnormalities in the HDL may contribute to their increased atherogenesis and excessive deposits of tissue sterols in the presence of low or low-normal concentrations of plasma cholesterol (165 +/- 25 mg/dl) and low density lipoproteins (LDL). The mean HDL-cholesterol concentration in the CTX plasmas was 14.5 +/- 3.2 mg/dl, about one-third the normal value. The low HDL-cholesterol reflects a low concentration and an abnormal lipid composition of the plasma HDL. Relative to normal HDL, the cholesteryl esters are low, free cholesterol and phospholipids essentially normal, and triglycerides increased. The ratio of apoprotein (apo) to total cholesterol in the HDL of CTX was two to three times greater than normal. In the CTX HDL, the ratio of apoAI to apoAII was high, the proportion of apoC low, and a normally minor form of apoAI increased relative to other forms. The HDL in electron micrographs appeared normal morphologically and in particle size. The abnormalities in lipoprotein distribution profile and composition of the plasma HDL result from metabolic defects that are not understood but may be linked to the genetic defect in bile acid synthesis in CTX. As a consequence, it is probable that the normal functions of the HDL, possibly including modulation of LDL-cholesterol uptake and the removal of excess cholesterol from peripheral tissues, are perturbed significantly in this disease.

Adult↗
PubMed1981

Computed tomography in cerebrotendinous xanthomatosis.

In nine patients with cerebrotendinous xanthomatosis (CTX), computed tomography (CT) demonstrated diffuse white matter hypodensity above and below the tentorium. This was attributed to sterol infiltration with secondary demyelination. In one patient, a focal right cerebellar hypodense lesion reflected a true xanthoma. These findings suggest that the neurologic symptoms, no matter how longstanding, result from metabolic encephalopathy rather than irreversible destruction of brain tissue by xanthomas.

Adolescent↗
PubMed1981

Regulation of bile acid synthesis. Measurement of cholesterol 7 alpha-hydroxylase activity in rat liver microsomal preparations in the absence of endogenous cholesterol.

A rapid procedure was developed to measure hepatic cholesterol 7 alpha-hydroxylase activity in the absence of endogenous microsomal cholesterol. This method involves the preparation of an acetone powder from the microsomal fraction of rat liver that retains its cholesterol 7 alpha-hydroxylase activity and contains virtually no endogenous cholesterol. The enzyme activity is measured in the presence of labeled exogenous cholesterol as the only substrate source, and can be expressed in terms of picomoles of product formed when a simple isotope incorporation procedure is employed. Optimal assay conditions were determined and the reproducibility of the acetone powder cholesterol 7 alpha-hydroxylase assay was established. A comparison of the proposed method with the previously used double isotope derivative procedure showed comparable enzyme activities in control rats and both methods exhibited an increase in the rate of hydroxylation after cholestyramine treatment and a decrease following cholic acid treatment. In contrast, the acetone powder assay did not show any change in cholesterol 7 alpha-hydroxylase activity during cholesterol feeding. These findings suggest that bile acid feeding influences the amount of active cholesterol 7 alpha-hydroxylase present in the liver whereas cholesterol feeding does not.

Animals↗
PubMed1981

Thin-layer chromatographic separation of conjugates of ursodeoxycholic acid from those of litho-, chenodeoxy-, deoxy-, and cholic acids.

Separation of the glycine and taurine conjugates of ursodeoxycholic acid from those of lithocholic acid, chenodeoxycholic acid, deoxycholic acid, and cholic acid by thin-layer chromatography is described. Thus, on running a silica gel G plate first in a solvent system of n-butanol-water 20:3 and then in a second solvent system of chloroform-isopropanol-acetic acid-water 30:20:4:1, all the above-mentioned conjugated bile acids are separated from one another. The application of this method to study the change in the biliary bile acid conjugation pattern in ursodeoxycholic acid-fed gallstone patients is described.

Chenodeoxycholic Acid↗
PubMed1980

Circular dichroism studies of keto-bile acids.

Circular dichroism curves for various saturated bile acid derivatives with carbonyl groups at carbon atoms 3,7, and 12 are presented and it is demonstrated that this method offers a convenient solution for the location of mono and diketo carbonyl groups in the bile acid molecule. From the shapes (n leads to II transition) of these CD curves the precise localization of the carbonyl groups and the stereochemistry of the A/B ring juncture can be determined.

Bile Acids and Salts↗
PubMed1980

A facile synthesis of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol.

A convenient procedure for the synthesis of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol via a modified homologation sequence of the intermediate 3 alpha,7 alpha,12 alpha-triformyloxy-24-oxo-25-diazo-25-homo-5 beta-cholane involving a homogeneous medium is described. This involves treating the intermediate alpha-diazoketone in methanol with a solution of silver benzoate in triethylamine. Grignard reaction of the resulting triformyloxy methyl homocholate yielded 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol. Large amounts of this bile alcohol were needed to further investigate the defect of cholic acid biosynthesis in patients with cerebrotendinous xanthomatosis (CTX).

Chemical Phenomena↗
PubMed1980

Biliary bile acids, bile alcohols, and sterols of Alligator mississippiensis.

Bile from Alligator mississippiensis was found to contain a mixture of more than twenty bile acids, bile alcohols, and neutral sterols. Bile acids and bile alcohols were purified by reversed-phase high performance liquid chromatography and thin-layer chromatography. Concentrations were measured by gas-liquid chromatography on 1% HiEFF-8BP and identifications were made by mass spectrometry. The major neutral sterols consisted of 98% cholesterol and 0.8% cholestanol. Bile acids recovered from the acidic fraction were 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestanoic acid (61%), 3 alpha, 7 alpha-dihydroxy-5 beta-cholestanoic acid (9%), 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 alpha-cholestanoic acid (8%), and 3-oxo-7 alpha, 12 alpha-dihydroxy-5 beta-cholestanoic acid (10%). Other C27 bile acids identified were: 3 alpha, 12 alpha-dihydroxy-5 beta-cholestanoic acid, 7-oxo-3 alpha, 12 alpha-dihydroxy-5 beta-cholestanoic acid, and 3-oxo-7 alpha, 12 alpha-dihydroxy-5 alpha-cholestanoic acid. Small quantities of C24 cholic, 5 alpha-cholic, chenodeoxycholic, and ursodeoxycholic acids were also detected, as were trace amounts of the C27 bile alcohols 5 alpha-cholestane-3 alpha, 7 alpha, 12 alpha, 26-tetrol, and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol. These results suggest that the alligator is acpable of synthesizing both the 5 alpha and 5 beta-isomers of the C27 bile acids. The small amounts of the C24 bile acids present might originate either from C27 bile acid or bile alcohol precursors or from exogenous sources.

Alligators and Crocodiles↗
PubMed1980

Differentiation between the 25R- and 25S-isomers of 5 beta-cholestane-3 alpha, 7 alpha, 26-triol by 13C NMR spectroscopy.

This study was designed to examine whether 13C nuclear magnetic resonance (NMR) spectroscopy can be used to differentiate between the 25R and 25S diastereoisomers of 5 beta-cholestane-3 alpha, 7 alpha, 26-triol, a key intermiediate in the biosynthetic pathway of chenodeoxycholic acid. Chemical shift values were assigned to the individual carbon atoms with the help of model compounds and multiplicity in the single-frequency off-resonance decoupled spectra. It was found that the corresponding carbons 1-20 afforded identical chemical shifts for both compounds, whereas five of the remaining side-chain carbons gave observed shift differences of 0.05-0.20 ppm. Thus 13C NMR can be used as an additional tool to distinguish between the two 5 beta-cholestanetriols isomeric at C-25.

Chemical Phenomena↗