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Biomedical subjects

G Salen

Publications and source records attributed to G Salen.

At least 253 records · Page 14Linked to original sources
PubMed1975

Toxicity of chenodeoxycholic acid in the rhesus monkey.

Chenodeoxycholic acid is an important drug for the treatment of cholesterol cholelithiasis in man. Although no toxicity has been demostrated in man, liver lesions develop in rhesus monkeys treated with chenodeoxycholic acid. To elucidate the mechanism of toxicity, chenodeoxycholic acid. To elucidate the mechanism of toxicity, chenodeoxycholic acid was fed daily to three groups of 6 animals each at the following dose: 10, 40, and 100 mg per kg; 2 separate animals were not treated and served as controls. After 1 month, the animals were killed. During the treatment period, most blood tests (e.g., blood count, blood urea nitrogen, albumin, SGOT, lactate dehydrogenase) remained within normal limits, but there was a significant dose-related increase in serum leucine aminopeptidase levels. The percentage of lithochlic acid, the 7-dehydroxylated bacterial metabolite of chenodeoxycholic acid, rose from 1% in the control animal to almost 14% in the 100 mg per kg-treated group. Liver biopsies obtained before treatment and at necropsy showed no significant changes. Thus, exposure of the liver to increased amounts of lithocholic acid during chenodeoxycholic acid treatment might result in elevation of serum leucine aminopeptidase activity.

Animals↗
PubMed1975

Hepatic cholesterol metabolism in patients with gallstones.

Relative rates of cholesterol and bile acid synthesis were estimated in patients with cholesterol gallstones and biliary obstruction by determining the hepatic activities of 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7 alpha-hydroxylase, the respective rate-determining enzymes for cholesterol and bile acid synthesis. As compared with eight control studies, 3-hydroxy-3-methylglutaryl-CoA reductase activity was 27% higher in 12 gallstone subjects, but 75% lower in 5 subjects with biliary obstruction. Cholesterol 7 alpha-hydroxylase activity was reduced in the gallstone (47% lower) and biliary obstruction (78% lower) subjects. Liver cholesterol concentrations were 56% higher in the gallstone and 53% higher in the biliary obstruction subjects than the control group. These findings suggest that the pathogenesis of gallstones is related to both increased cholesterol synthesis and decreased bile acid formation, whereas cholesterol accumulates in biliary obstruction because of defective removal since cholesterol production is low.

Adult↗
PubMed1974

Increased formation of ursodeoxycholic acid in patients treated with chenodeoxycholic acid.

The formation of ursodeoxycholic acid, the 7 beta-hydroxy epimer of chenodeoxycholic acid, was investigated in three subjects with cerebrotendinous xanthomatosis and in four subjects with gallstones. Total biliary bile acid composition was analyzed by gas-liquid chromatography before and after 4 months of treatment with 0.75 g/day of chenodeoxycholic acid. Individual bile acids were identified by mass spectrometry. Before treatment, bile from cerebrotendinous xanthomatosis (CTX) subjects contained cholic acid, 85%; chenodeoxycholic acid, 7%; deoxycholic acid, 3%; allocholic acid, 3%; and unidentified steroids, 2%; while bile from gallstone subjects contained cholic acid, 45%; chenodeoxycholic acid, 43%; deoxycholic acid, 11%, and lithocholic acid, 1%. In all subjects, 4 months of chenodeoxycholic acid therapy increased the proportion of this bile acid to approximately 80% and decreased cholic acid to 3% of the total biliary bile acids, the remaining 17% of bile acids were identified as ursodeoxycholic acid. After the intravenous injection of [3H]chenodeoxycholic acid, the specific activity of biliary ursodeoxycholic acid exceeded the specific activity of chenodeoxycholic acid, and the resulting specific activity decay curves suggested precursor-product relationships. When [3H]7-ketolithocholic acid was administrated to another patient treated with chenodeoxycholic acid, radioactivity was detected in both the ursodeoxycholic acid and chenodeoxycholic acid fractions. These results indicate that substantial amounts of ursodeoxycholic acid are formed in patients treated with chenodeoxycholic acid. The ursodeoxycholic acid was synthesized from chenodeoxycholic acid presumably via 7-ketolithocholic acid.

Bile Acids and Salts↗
PubMed1974

A biochemical abnormality in cerebrotendinous xanthomatosis. Impairment of bile acid biosynthesis associated with incomplete degradation of the cholesterol side chain.

Bile acid production in cerebrotendinous xanthomatosis (CTX) is subnormal, yet the activity of cholesterol 7alpha-hydroxylase, the rate-determining enzyme of bile acid synthesis, is elevated. To explain this discrepancy, bile acid precursors were sought in bile and feces of three CTX subjects. Over 10% of the total sterols excreted in bile and feces consisted of compounds more polar than cholesterol. Chromatographic analysis of the polar fractions in conjunction with gasliquid chromatography (GLC)-mass spectrometry indicated two major constituents, 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol and 5beta-cholestane-3alpha,7alpha,12alpha,24xi,25-pentol. After i.v. injection of [4-(14)C]cholesterol both bile alcohols were radioactive proving that they were derived from cholesterol. The accumulation of alcohols hydroxylated at C-25 and C-24,25 suggests that decreased bile acid synthesis in CTX results from impaired oxidation of the cholesterol side chain. This finding and the virtual absence of intermediates hydroxylated at C-26 indicate that current views of the major pathway of bile acid synthesis may require revision.

Alcohols↗
PubMed1974

Determination of hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity in man.

Procedures were developed for the determination of the activity of the microsomal enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase, EC 1.1.1.34) in human liver. The enzyme assay could be carried out with as little as 20 mg of fresh liver tissue, thus making the method applicable to specimens obtained by percutaneous liver biopsy. Experiments were carried out to determine optimal assay conditions and to establish the identity and radiopurity of the reaction product formed from 3-(14)C-labeled 3-hydroxy-3-methylglutaryl CoA. The specific activity of the enzyme was measured in a number of patients with different disorders of lipid metabolism.

Alcohol Oxidoreductases↗
PubMed1974

Transformation of 5 alpha-cholest-7-en-3 beta-ol to cholesterol and cholestanol in cerebrotendinous xanthomatosis.

The metabolism of Delta(7)-cholestenol, cholesterol, and cholestanol was examined in a patient with cerebrotendinous xanthomatosis after intravenous pulse-labeling with a mixture of dl-[2-(14)C]mevalonate and stereospecific 3S,4S,3R,4R-[4-(3)H]mevalonate. Silver nitrate and reversed-phase thin-layer chromatography were used to purify the sterols isolated from the feces, and their identities were confirmed by gas-liquid chromatography-mass spectrometry. The specific activities were determined and plotted as a function of time. Isotope ratio measurements and specific activity decay curves showed that sterol synthesis proceeded in the following sequence: mevalonate, squalene, lanosterol, Delta(7)-cholestenol, cholesterol, cholestanol. Labeled cholesterol precursors might be advantageously used to measure changes in cholesterol synthesis because they appear to equilibrate rapidly and have very short turnover times.

Carbon Radioisotopes↗
PubMed1973

The metabolism of cholestanol, cholesterol, and bile acids in cerebrotendinous xanthomatosis.

The metabolism of cholesterol and its 5-dihydro derivative, cholestanol, was investigated by means of sterol balance and isotope kinetic techniques in 3 subjects with cerebrotendinous xanthomatosis (CTX) and 11 other individuals. All subjects were hospitalized on a metabolic ward and were fed diets practically free of cholesterol and cholestanol. After the intravenous administration of [1,2-(3)H]cholestanol, the radioactive sterol was transported and esterified in plasma lipoproteins in an identical manner to cholesterol. In these short-term experiments, the specific activity-time curves of plasma cholestanol conformed to two-pool models in both the CTX and control groups. However, cholestanol plasma concentrations, total body miscible pools, and daily synthesis rates were two to five times greater in the CTX than control individuals. The short-term specific activity decay curves of plasma [4-(14)C]cholesterol also conformed to two-pool models in both groups. However, in the CTX subjects the decay was more rapid, and daily cholesterol synthesis was nearly double that of the control subjects. Plasma concentrations and the sizes of the rapidly turning over pool of exchangeable cholesterol were apparently small in the CTX subjects, and these measurements did not correlate with the large cholesterol deposits found in tendon and tuberous xanthomas. Despite active cholesterol synthesis, bile acid formation was subnormal in the CTX subjects. However, bile acid sequestration was accompanied by a rise in plasma cholestanol levels and greatly augmented fecal cholestanol outputs. In contrast, the administration of clofibrate lowered plasma cholesterol levels 50% and presumably reduced synthesis in the CTX subjects. Plasma cholesterol concentrations and fecal steroid excretion did not change significantly during this therapy. These findings indicate that the excessive tissue deposits of cholesterol and cholestanol that characterize CTX were associated with hyperactive neutral sterol synthesis. The demonstration of subnormal bile acid formation suggests that defective bile acid synthesis may predispose to the neutral sterol abnormalities.

Adult↗
PubMed1972

Biosynthesis of 5 -cholestan-3 -ol in cerebrotendinous xanthomatosis.

Cerebrotendinous Xanthomatosis is a rare, inherited disease characterized by an extraordinary accumulation of cholestanol in all tissues, xanthomatous deposits in the brain, lungs, and Achilles tendons, premature atherosclerosis, and low plasma cholesterol concentrations. In two patients with the disease, the biosynthesis of cholestanol was examined by different techniques. After cholesterol-4-(14)C was injected intravenously into one patient, cholestanol and cholesterol isolated from the bile on 3 different days over the ensuing week contained significant radioactivity. The specific radioactivity-time curves for cholesterol-(14)C and cholestanol-(14)C suggested a precursor product relationship and provided additional evidence for the transformation of cholesterol into cholestanol. The second patient received intravenously a mixture of mevalonate-2-(14)C and stereospecifically labeled mevalonate-3R,4R-(3)H. Again cholesterol and cholestanol were isolated from the bile, and the (3)H/(14)C ratio in both sterols was almost the same. This experiment again demonstrated that the biosynthetic path of cholestanol proceeded through cholesterol and not directly from earlier 5alpha-H-saturated precursors. These two independent lines of evidence indicate that the extraordinary deposition of cholestanol in Cerebrotendinous Xanthomatosis arises from cholesterol presumably through the accentuation of the normal biosynthetic pathway.

Adult↗
PubMed1972

Mechanisms of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia.

The influence of clofibrate on cholesterol metabolism in patients with hyperlipidemia was studied by means of sterol balance and isotope kinetic techniques and by measurements of flow rates of cholesterol through the biliary tract. Long-term balance studies were carried out on a metabolic ward in 24 patients with all currently recognized types of hyperlipidemia; in five other patients with hypercholesterolemia, pool sizes and turnover rates of cholesterol were defined by compartmental analysis before and after three years' daily administration of the drug. Except in fat-induced hypertriglyceridemia (two patients), clofibrate caused reduced plasma levels of triglycerides and cholesterol in all categories of hyperlipidemia. As a general rule, excretion of cholesterol into bile and feces was significantly increased and fecal bile acid excretion was decreased, regardless of the type of lipoprotein abnormality. Despite a net increase in steroid excretion in most patients with hyperlipidemia, cholesterol synthesis was not increased; indeed, in many patients synthesis appeared to be decreased. While the data obtained in 29 patients were not always consistent, the bulk of the evidence suggests that, in all forms of hyperlipidemia except fat-induced hyperglyceridemia, the drug causes an increased output of cholesterol while simultaneously inhibiting any compensatory increase in cholesterol synthesis. Therefore, it appeared that the increased excretion of steroids was most likely derived from cholesterol stored in tissues. This conclusion was strengthened by finding that long-term administration of the drug can cause marked reduction in body pools of cholesterol. These findings are reflected clinically by resolution of skin and tendon xanthomatosis. However, it is not yet known whether the accumulation of cholesterol in arterial walls that is part of the process of atherogenesis can be inhibited or reversed by the drug.

Adult↗
PubMed1970

Metabolism of beta-sitosterol in man.

The metabolism of beta-sitosterol was compared to that of cholesterol in 12 patients. Sterol balance methods were supplemented by radiosterol studies, with the following results. (a) Plasma concentrations of beta-sitosterol ranged from 0.30 to 1.02 mg/100 ml plasma in patients on intakes of beta-sitosterol typical of the American diet. Plasma levels were raised little when intakes were increased greatly, and on fixed intakes they were constant from week to week. On diets devoid of plant sterols, the plasma and feces rapidly became free of beta-sitosterol. (b) The percentage of esterified beta-sitosterol in the plasma was the same as for cholesterol. However, the rate of esterification of beta-sitosterol was slower than that for cholesterol. (c) Specific activity-time curves after simultaneous pulse labeling with beta-sitosterol-(3)H and cholesterol-(14)C conformed to two-pool models. The two exponential half-lives of beta-sitosterol were much shorter than for cholesterol, and pool sizes were much smaller. Values of turnover for beta-sitosterol obtained by the sterol balance method agreed closely with those derived by use of the two-pool model. There was no endogenous synthesis of beta-sitosterol in the patients studied; hence, daily turnover of beta-sitosterol equaled its daily absorption. Absorption of beta-sitosterol was 5% (or less) of daily intake, while cholesterol absorption ranged from 45 to 54% of intake. (d) About 20% of the absorbed beta-sitosterol was converted to cholic and chenodeoxycholic acids. The remainder was excreted in bile as free sterol; this excretion was more rapid than that of cholesterol. (e) The employment of beta-sitosterol as an internal standard to correct for losses of cholesterol in sterol balance studies is further validated by the results presented here.

Adult↗
PubMed1968

Dietary beta-sitosterol as an internal standard to correct for cholesterol losses in sterol balance studies.

In the course of carrying out sterol balance studies in 19 patients, we gathered the following evidence that, in some but not all patients, considerable amounts of neutral sterols are "lost" during their passage through the intestinal tract. (a) Since plant sterols are largely nonabsorbable in man, they should be totally recovered in the feces; yet in many patients significantly less plant sterol than expected was recovered, the loss amounting to as much as 56% of daily intake. (b) In two patients in whom cholesterol-(14)C and beta-sitosterol-(3)H were instilled into the terminal ileum, from which neither sterol is absorbed, the feces contained 25% less of each isotope than was instilled. (c) In four patients fed radioactive cholesterol daily until the isotopic steady state was closely approximated, 28-50% of the isotope could not be accounted for. On the other hand, in five patients fed radioactive bile acids until the isotopic steady state was approximated, input equalled output as predicted. Since the amount of -sitosterol absorbed in man is limited (5% or less), this sterol can be used as an internal standard for upward correction of the figure obtained for the amount of neutral steroids excreted. The use of beta-sitosterol for this purpose is based on three considerations: (a) it passes through the intestine in the same physicochemical state as cholesterol; (b) it accompanies cholesterol at every step of its isolation and chromatographic measurement; and (c) it is lost to the same extent as cholesterol. Excretion data for fecal neutral steroids can therefore be corrected for irregular fecal flow as well as for the "unexpected loss" referred to. This loss seems to be due not to errors in stool collection or to technical errors, but to intestinal bacterial degradation of neutral 3beta-OH,Delta(5)-sterols to products not recognized as steroids in the analytical methods used.

Absorption↗