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Biomedical subjects

G Salen

Publications and source records attributed to G Salen.

At least 163 records · Page 9Linked to original sources
PubMed1989

A bile alcohol sulfate as a major component in the bile of the small skate (Raja erinacea).

The nature of bile alcohols and bile acids in gall-bladder and hepatic bile from perfused livers of the small skate (Raja erinacea) has been investigated. The main bile alcohol sulfate was isolated by thin-layer chromatography and analyzed by fast atom bombardment mass spectrometry and 13C NMR. Following solvolysis and purification on Lipidex-DEAP, the bile alcohol profile was measured by capillary gas-liquid chromatography-electron impact mass spectrometry. Based on these studies and on comparison with authentic scymmnol sulfate and scymnol, the main bile alcohol was identified as 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 xi,26,27-hexol sulfate. The mean +/- SD concentration in gallbladder bile from five different skates was 24.6 +/- 8.7 mmol/l. Only 0.1 mmol/l of cholic acid and its conjugates was found in a pool of skate bile. The main bile alcohol sulfate in the bile of the small skate seems to be a metabolic end product, present in a concentration comparable to that of bile salts in mammals.

Animals↗
PubMed1989

Chenodeoxycholic acid normalizes elevated lipoprotein secretion and catabolism in cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare inherited lipid storage disease caused by a defect in bile acid synthesis in which cholesterol and its product cholestanol are deposited in neurological and vascular tissue. Therapy with chenodeoxycholic acid but not with the 7 beta-epimeric ursodeoxycholic acid is usually successful. In an untreated patient, total and low density lipoprotein (LDL) cholesterol were found to be low (134 +/- 11 and 78 +/- 8 mg/dl, respectively). The production rate (PR) and fractional catabolic rate (FCR) of very low density (VLDL) apolipoprotein B (apoB) were, however, both markedly increased (34.7 mg/kg per day and 13.7 pools/day, respectively vs. 15.1 +/- 5.0 mg/kg per day and 6.2 +/- 3.8 pools/day in controls) while the PR and FCR of LDL apoB were moderately elevated (16.3 mg/kg per day and 0.65 pools/day, respectively vs. 12.9 +/- 1.2 mg/kg per day and 0.52 +/- 0.10 pools/day in controls). After 1 month of 750 mg/day of chenodeoxycholic acid, the FCR and PR of both VLDL and LDL apoB became normal while total plasma cholesterol increased significantly to 145 +/- 18 mg/dl. In a second patient who had been receiving 750 mg/day of chenodeoxycholic acid for 6 months lipoprotein kinetics were normal. These parameters did not change when the subject was switched to 750 mg/day ursodeoxycholic acid. We postulate that cholesterol biosynthesis in CTX is derepressed by a diminished hepatic pool of chenodeoxycholic acid and that the elevated secretion of apoB is a response to the increased rate of cholesterol production.

Adult↗
PubMed1989

Characterization of sarcosylsarcoursodeoxycholic acid formed during the synthesis of sarcoursodeoxycholic acid.

This report describes the isolation of sarcosylsarcosine conjugate of ursodeoxycholic acid (UDCA) formed during the synthesis of sarcoUDCA by the mixed anhydride method. The compound was characterized by its chemical ionization mass spectrum. The diamino acid conjugate was formed only when the free amino acid was used for conjugation. This was confirmed by the isolation of glycylglycoUDCA during the conjugation of UDCA with free glycine but not with glycine ethyl ester hydrochloride. Pure sarcoUDCA was prepared by conjugation of UDCA with sarocisine methyl ester hydrochloride while sarcoUDCA on further reaction with the protected sarcosine derivative gave pure sarcosylsarcoUDCA in 52% yield.

Deoxycholic Acid↗
PubMed1988

Pregnancy in women with cerebrotendinous xanthomatosis (CTX): high risk condition for fetus and newborn infant?

Cerebrotendinous xanthomatosis (CTX), is one of the few autosomal recessive progressive storage diseases allowing affected individuals to reproduce. We investigated 38 CTX patients and most of their families. The possibility of a high risk situation for the fetus and/or the apparently healthy newborn infant born to CTX mothers and female carriers of the gene is discussed for genetic counseling purposes and in view of available treatment.

Abortion, Spontaneous↗
PubMed1988

The effect of abnormal plasma and cellular sterol content and composition on low density lipoprotein uptake and degradation by monocytes and lymphocytes in sitosterolemia with xanthomatosis.

The hypothesis that abnormal low density lipoprotein (LDL) sterol content and composition in sitosterolemia with xanthomatosis affects LDL uptake and/or degradation was tested. Monocytes and lymphocytes from three patients and 12 age- and sex-matched controls were incubated at 37 degrees C in lipid-free medium with 125I-labeled LDL prepared from sitosterolemic patients (LDLs) and controls (LDLn) in the presence or absence of excess unlabeled lipoproteins. Normal monocytes and lymphocytes took up and degraded LDLs 13% to 30% less than LDLn (P less than .05). Sitosterolemic monocytes and lymphocytes degraded LDLn 13% and LDLs 67% more actively than control cells (P less than .05). Sitosterolemic monocytes contained three times more sterols and stanols than controls (P less than .01), of which 12% were plant sterols and 2% were 5 alpha-saturated stanols. In one patient, stimulating bile acid synthesis by ileal bypass surgery reduced plasma and monocyte sterol and stanol concentrations about 60%, and was associated with a 40% to 50% increase in LDLn and LDLs receptor-mediated degradation. The decreased uptake and degradation of LDLs relative to LDLn by normal cells suggest that abnormal plant sterols in LDLs may reduce its affinity for the native LDL receptor. Increased receptor-mediated uptake and degradation of LDLs by sitosterolemic cells in the presence of high cellular sterol content may result from failure of the sitosterolemic cells to down-regulate LDL receptor synthesis. Ileal bypass surgery increased cellular LDL receptor activity, reduced plasma and cellular sterol concentrations, and may diminish the risk of premature atherosclerosis in sitosterolemia.

Adult↗
PubMed1988

Competitive inhibition of bile acid synthesis by endogenous cholestanol and sitosterol in sitosterolemia with xanthomatosis. Effect on cholesterol 7 alpha-hydroxylase.

The 7 alpha-hydroxylation of two cholesterol analogues, sitosterol and cholestanol, and their effect on the 7 alpha-hydroxylation of cholesterol were measured in rat and human hepatic microsomes. In untreated rat liver microsomes, the 7 alpha-hydroxylation of cholesterol was higher than that of cholestanol (1.4-fold) and sitosterol (30-fold). After removal of endogenous sterols from the microsomes by acetone treatment, the 7 alpha-hydroxylation of cholesterol was similar to that of cholestanol and only fourfold higher than that of sitosterol. Cholestanol and sitosterol competitively inhibited cholesterol 7 alpha-hydroxylase in both rat and human liver microsomes, with cholestanol the more potent inhibitor. Patients with sitosterolemia with xanthomatosis, who have elevated microsomal cholestanol and sitosterol, showed reduced cholesterol 7 alpha-hydroxylase activity relative to the activity in control subjects (13.9 and 14.7 vs. 20.3 +/- 0.9 pmol/nmol P-450 per min, P less than 0.01). Enzyme activity in these patients was 40% higher when measured in microsomes from which competing sterols had been removed. Ileal bypass surgery in one sitosterolemic patient decreased plasma cholestanol and sitosterol concentrations and resulted in a 30% increase in hepatic microsomal cholesterol 7 alpha-hydroxylase activity. Cholesterol 7 alpha-hydroxylase appears to have a specific apolar binding site for the side chain of cholesterol and is affected by the presence of cholestanol and sitosterol in the microsomal substrate pool. Reduced bile acid synthesis in sitosterolemia with xanthomatosis may be related to the inhibition of cholesterol 7 alpha-hydroxylase activity by endogenous cholesterol analogues.

Adolescent↗
PubMed1988

Psychiatric disorders in patients with cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis is a familial recessive disorder. Patients with the disorder present with tendon xanthomas, juvenile cataracts, dementia, and pyramidal and cerebellar abnormalities but have normal plasma cholesterol. High plasma cholestanol concentrations and abnormal bile acid metabolism are specific for this disease. The authors describe four patients with cerebrotendinous xanthomatosis and prominent psychiatric symptoms. In three of these patients appropriate diagnosis and treatment were delayed for years because the presence of cerebrotendinous xanthomatosis was not recognized. Early recognition of this potentially lethal disease is important because both the psychiatric and neurological symptoms respond to treatment with chenodeoxycholic acid.

Achilles Tendon↗
PubMed1988

Clinical perspective on the treatment of gallstones with ursodeoxycholic acid.

Ursodeoxycholic acid (ursodiol) is a naturally occurring bile acid that constitutes about 1-2% of the bile acids in human bile. Although well known for more than 20 years in Japan as a treatment for biliary distress and dyspepsia, ursodiol has been tested as a gallstone-dissolving agent only since 1976. Successful dissolution occurs in 30-80% of subjects with radiolucent gallstones, depending on the size and number of the stones. Calcified or pigment stones do not respond to this treatment. The current theory of the pathogenesis of gallstones is that lithogenic bile, which is supersaturated with cholesterol, is secreted by the liver and is not produced in the gallbladder. Thus, although stones form in the gallbladder, defective hepatic cholesterol and bile acid metabolism are responsible for the abnormal bile. Gallstone-prone individuals show increased hepatocholesterol formation and reduced bile acid synthesis. As the micellar solubility limit in bile is exceeded, cholesterol microcrystals precipitate. Four factors account for ursodiol's effectiveness in gallstone dissolution: (a) biliary cholesterol secretion is diminished markedly during therapy; (b) hepatic bile acid synthesis is not inhibited by ursodiol; (c) the 7 beta-hydroxy group of ursodiol resists bacterial dehydroxylation, which lowers the amount of lithocholic acid formed and the cholestasis and liver damage it can cause; and (d) ursodiol is virtually free of side effects and toxicity; less than 1% of subjects experience transient diarrhea, which does not require discontinuation of treatment, and liver function tests remain normal. In about 50% of subjects, stones may recur within 84 months, and can be retreated with ursodiol.

Bile↗
PubMed1987

Increased concentrations of cholestanol and apolipoprotein B in the cerebrospinal fluid of patients with cerebrotendinous xanthomatosis. Effect of chenodeoxycholic acid.

We investigated the effect of chenodeoxycholic acid on cerebrospinal fluid sterol and protein composition in six patients with cerebrotendinous xanthomatosis, a progressive neurologic disease, and in 11 control subjects. In the cerebrospinal fluid from the controls, the mean (+/- SD) levels of cholesterol and cholestanol were 400 +/- 300 and 4 +/- 7 micrograms per deciliter, respectively. The levels were almost 1.5 and 20 times higher in cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis. Cholestanol levels were also markedly elevated in the plasma of untreated patients, but their plasma cholesterol levels (215 +/- 61 mg per deciliter) were not different from control values. Treatment with chenodeoxycholic acid reduced cerebrospinal fluid cholesterol by 34 percent and cholestanol threefold. Plasma cholestanol levels also decreased sharply. Normal cerebrospinal fluid contained small quantities of albumin, apolipoproteins, and lecithin:cholesterol acyltransferase. In cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis, immunoreactive apolipoprotein B or apolipoprotein B fragment was increased about 100-fold and albumin about 3.5-fold; apolipoprotein AI, apolipoprotein D, and lecithin:cholesterol acyltransferase were 1.5 to 3 times more concentrated. Apolipoprotein AIV and apolipoprotein E concentrations were comparable to those in controls, and apolipoprotein AII was considerably decreased. During treatment, the concentrations of albumin and apolipoproteins AI and B declined. These results suggest that increased cerebrospinal fluid sterols are derived from plasma lipoproteins by means of a defective blood-brain barrier in patients with cerebrotendinous xanthomatosis. Therapy with chenodeoxycholic acid reestablished selective permeability of the blood-brain barrier and normalized the concentrations of sterol and apolipoprotein in the cerebrospinal fluid.

Albumins↗
PubMed1987

Increased plasma bile alcohol glucuronides in patients with cerebrotendinous xanthomatosis: effect of chenodeoxycholic acid.

Large quantities of C27 bile alcohols hydroxylated at C-25 are excreted in the bile and urine of patients with cerebrotendinous xanthomatosis, a lipid storage disease that results from defective bile acid synthesis. The presence of both biliary and urinary bile alcohols reflects impaired bile acid synthesis. After treatment of samples with beta-glucuronidase, plasma bile alcohols were quantitated by gas-liquid chromatography-mass spectrometry. 5 beta-Cholestane-3 alpha,7 alpha,12 alpha,25-tetrol (334 micrograms/dl) was found to be the major bile alcohol, followed by 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23R,25-pentol (65 micrograms/dl), and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24(R and S),25-pentols (62.5 micrograms/dl and 64.5 micrograms/dl, respectively) in the plasma of these patients. When compared to biliary and urinary bile alcohol excretions, the plasma pattern resembled bile where 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol glucuronide predominated. In contrast, urinary bile alcohols were composed chiefly of 5 beta-cholestanepentol glucuronides with only small amounts of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol glucuronide. Treatment with chenodeoxycholic acid, which suppresses abnormal bile acid synthesis in these patients, reduced plasma bile alcohol concentrations dramatically. These results show that large quantities of bile alcohol glucuronides, particularly 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrolglucuronide, circulate in plasma of patients with cerebrotendinous xanthomatosis. The plasma bile alcohols closely resemble biliary bile alcohols which indicates their hepatic origin. The large quantities of polyhydroxylated bile alcohols in the urine may suggest their formation, at least in part, from 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol by renal hydroxylating mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Effect of ursodeoxycholic acid and chenodeoxycholic acid on cholesterol and bile acid metabolism.

Orally administered UDCA dramatically reduces the secretion of cholesterol into the bile. During UDCA therapy cholesterol balance is maintained by a reduction in both the relative and absolute absorption of cholesterol and, perhaps, by a combined moderate enhancement of bile acid synthesis and a suppression of cholesterol production. The percentage of UDCA in the bile is limited by the inability of UDCA to suppress bile acid synthesis from cholesterol and by the conversion of UDCA to CDCA by the intestinal bacteria.

Animals↗
PubMed1986

Ursodeoxycholic acid, 7-ketolithocholic acid, and chenodeoxycholic acid are primary bile acids of the nutria (Myocastor coypus).

Because ursodeoxycholic and chenodeoxycholic acids are interconverted in humans via 7-ketolithocholic acid, bile acid metabolism was studied in the nutria (Myocastor coypus), the bile of which is known to contain these three bile acids. Relative concentrations of ursodeoxycholic (37% +/- 20%), 7-ketolithocholic (33% +/- 17%), and chenodeoxycholic (17% +/- 9%) acids in gallbladder bile were unchanged by 5-20 h of complete biliary diversion (n = 7). Injection of either [14C]cholesterol, [14C]ursodeoxycholic, [14C]7-ketolithocholic acid, or a mixture of [7 beta-3H]chenodeoxycholic acid and [14C]chenodeoxycholic acid into bile fistula nutria demonstrated that all three bile acids can be synthesized hepatically from cholesterol, that they are interconverted sparingly (2%-5%) by the liver, but that 7-ketolithocholic acid is an intermediate in the hepatic transformation of chenodeoxycholic acid to ursodeoxycholic acid. An animal that had been fed antibiotics showed an unusually elevated concentration of ursodeoxycholic acid in gallbladder and hepatic bile, suggesting that bacterial transformation of ursodeoxycholic acid in the intestine may be a source of some biliary chenodeoxycholic acid and 7-ketolithocholic acid.

Animals↗
PubMed1986

Configuration at C-25 in 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol excreted by patients with cerebrotendinous xanthomatosis: circular dichroism and 13C-NMR studies.

The configuration at C-25 in 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,25,26-pentol isolated from the bile and feces of patients with cerebrotendinous xanthomtosis (CTX) was determined from the lanthanide-induced circular dichroism (CD) Cotton effects and 13C-NMR measurements. Under anhydrous conditions, CD spectra of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,25,26-pentol in the presence of Eu(fod)3 exhibited a large induced negative Cotton effect at 320 nm. On the basis of the empirical rule (primary-tertiary-alpha-diols) in which R compounds have positive Cotton effects and S compounds have negative Cotton effects at 320 nm, it was concluded that 25,26-pentol has the 1,2,glycol structure with C-25 having the S-configuration. This assignment was based upon comparison with model compounds, 25(R and S),26-dihydroxy cholesterols and 25(R and S),26-dihydroxy cholecalciferols whose single-crystal X-ray structure and 13C-NMR studies have been performed. It is suggested that these data may be helpful to clarify the stereospecificity of the hydroxylation of the terminal methyl group of the cholesterol side chain in CTX.

Brain Diseases↗
PubMed1985

Peripheral neuropathy in cerebrotendinous xanthomatosis.

We performed a sural nerve biopsy in a patient with cerebrotendinous xanthomatosis (CTX) because of electrophysiologic evidence of peripheral neuropathy. The sections showed a striking loss of myelinated axons, the distribution of which suggested a compressive and/or ischemic process. Biochemical analysis disclosed large amounts of cholestanol, a cholesterol derivative that characteristically accumulates in CTX. However, the biochemical abnormality was not associated with any obvious structural alterations in the myelin lamellae or with abnormal storage material in Schwann's cells.

Achilles Tendon↗
PubMed1985

Treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid.

We describe a patient with cerebrotendinous xanthomatosis who was treated for one year with chenodeoxycholic acid. Modest clinical improvement was accompanied by marked improvement in visual and brainstem auditory evoked potentials. Improved central nervous system function coincided with return of plasma and cerebrospinal fluid cholestanol levels to normal.

Adult↗
PubMed1985

Ursodeoxycholic acid treatment of bile reflux gastritis.

Intractable epigastric pain associated with nausea and bilious vomiting often follows gastric surgery and has been attributed to reflux of bile and the irritating effects of endogenous bile acids on the gastric remnant. To test the effect of changing bile acid composition of the refluxed material on the symptoms and gastric mucosal histology, 12 patients with symptomatic alkaline reflux gastritis were treated for 1 mo with placebo and for 1 mo with ursodeoxycholic acid, 1000 mg/day. Before treatment, all patients were symptomatic and manifested epigastric pain, nausea, and bilious vomiting. The gastric mucosa was erythematous, friable, and bile stained, and the histology revealed chronic inflammation. No significant change in symptoms was noted during administration of placebo. In contrast, ursodeoxycholic acid treatment resulted in a profound decrease in the intensity and frequency of pain and almost abolished nausea and vomiting. During bile acid therapy the proportion of ursodeoxycholic acid in gastric bile rose to 50% of total bile acids, whereas cholic and deoxycholic acids decreased and chenodeoxycholic acid remained unchanged. The macroscopic and microscopic appearance of the gastric mucosa, however, did not change after 1 mo of ursodeoxycholic acid treatment. These results suggest that increasing the proportion of ursodeoxycholic acid in refluxed gastric bile reduces the pain and frequency of symptoms associated with bile reflux.

Adult↗
PubMed1985

Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26.

To examine the defect in side-chain oxidation during the formation of bile acids in cerebrotendinous xanthomatosis, we measured in vitro hepatic microsomal hydroxylations at C-12 and C-25 and mitochondrial hydroxylation at C-26 and related them to the pool size and synthesis rates of cholic acid and chenodeoxycholic acid as determined by the isotope dilution technique. Hepatic microsomes and mitochondria were prepared from seven subjects with cerebrotendinous xanthomatosis and five controls. Primary bile acid synthesis was markedly reduced in cerebrotendinous xanthomatosis as follows: cholic acid, 133 +/- 30 vs. 260 +/- 60 mg/d in controls; and chenodeoxycholic acid, 22 +/- 10 vs. 150 +/- 30 mg/d in controls. As postulated for chenodeoxycholic acid synthesis, mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha-diol was present in all specimens and was 30-fold more active than the corresponding microsomal 25-hydroxylation. However, mean mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha-diol was less active in cerebrotendinous xanthomatosis than in controls: 59 +/- 17 compared with 126 +/- 21 pmol/mg protein per min. As for cholic acid synthesis, microsomal 25-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was substantially higher in cerebrotendinous xanthomatosis and control preparations (620 +/- 103 and 515 +/- 64 pmol/mg protein per min, respectively) than the corresponding control mitochondrial 26-hydroxylation of the same substrate (165 +/- 25 pmol/mg protein per min). Moreover in cerebrotendinous xanthomatosis, mitochondrial 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol-26-hydroxylase activity was one-seventh as great as in controls. Hepatic microsomal 12 alpha-hydroxylation, which may be rate-controlling for the cholic acid pathway, was three times more active in cerebrotendinous xanthomatosis than in controls: 1,600 vs. 500 pmol/mg protein per min. These results demonstrate severely depressed primary bile acid synthesis in cerebrotendinous xanthomatosis with a reduction in chenodeoxycholic acid formation and pool size disproportionately greater than that for cholic acid. The deficiency of chenodeoxycholic acid can be accounted for by hyperactive microsomal 12 alpha-hydroxylation that diverts precursors into the cholic acid pathway combined with decreased side-chain oxidation (mitochondrial 26-hydroxylation). However, side-chain oxidation in cholic acid biosynthesis may be initiated via microsomal 25-hydroxylation of 5beta-cholestane-3alpha,7alpha,12alpha-triol was substantially lower in control and cerebrotendinous xanthomatosis liver. Thus, separate mechanisms may exist for the cleavage of the cholesterol side chain in cholic acid and chenodeoxycholic acid biosynthesis.

Adult↗