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Biomedical subjects

E H Mosbach

Publications and source records attributed to E H Mosbach.

At least 127 records · Page 7Linked to original sources
PubMed1975

New bile alcohols--synthesis of 5beta-cholestane-3alpha, 7alpha, 25-triol and 5beta-cholestane-3alpha, 7alpha, 25-24 (14C)-triol.

5beta-Cholestane-3alpha, 7alpha, 25-triol and 5beta-cholestane-3alpha, 7alpha, 25-24(14-C)-triol were synthesized from 3alpha, 7alpha-dihydroxy-5beta-cholanoic acid (chenodeoxycholic acid). Chenodeoxycholic acid was converted to the diformoxy derivative (II) using formic acid. Reaction of II with thionyl chloride yielded the acid chloride which was treated with diazomethane (CH-2-N-2 or 14-CH-2-N-2) to produce 3alpha, 7alpha-diformoxy-24-oxo-25-diazo-25-homocholane (III, A or B). 25-Homochenodeoxycholic acid (IV, A or B) was formed from III by means of the Wolff rearrangement of the Arndt-Eistert synthesis. The methyl ester of V (A or B) was treated with methyl magnesium iodidi in ether to provide the desired triol, VI (A and B). The triol was identified by mass spectrometry and elemental analysis and was characterized by thin-layer and gas-liquid chromatography. The 3alpha, 7alpha, 25-triol is of possible significance as an intermediate in the pathway of bile acid formation from cholesterol.

Bile↗
PubMed1975

Bile alcohol metabolism in man. Conversion of 5beta-cholestane-3alpha, 7alpha,12alpha, 25-tetrol to cholic acid.

To study the role of C25-HYDROXY BILE ALCOHOLS AS PRECURSORS OF CHOlic acid, [G-3-H]5beta-cholestane-3alpha,7alpha12alpha,25-tetrol was administered intravenously to two subjects with cerebrotendinous xanthomatosis (CTX) and two normal individuals. One day after pulse labeling, radioactivity was present in the cholic acid isolated from the bile and feces of the subjects with CTX and the bile of the normal individuals. In the two normal subjects, the sp act decay curves of [G-3-H]-cholic acid were exponential, and no traces of [G-3-H]-5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol were detected. In contrast, appreciable quantities of labeled 5beta-cholestane-3alpha,-7aopha,12alpha,25-tetrol were present in the bile and feces of the CTX subjects. The sp act vs. time curves of fecal [G-3-H]5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol and [G-3-H]-cholic acid showed a precursor-product relationship. Although these results suggest that 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol may be a precursor of cholic acid in man, the possibility that C26-hydroxy intermediates represent the normal pathway can not be excluded.

Alcohols↗
PubMed1975

Isotope derivative assay of microsomal cholesterol 7 alpha-hydroxylase.

A rapid method was developed to measure cholesterol 7 alpha-hydroxylase activity of hepatic microsomes by the direct determination of the mass of 7 alpha-hydroxycholesterol formed. The method is based on the quantitative acetylation of the incubation mixture with [-3H]acetic anhydride and the separation of the biosynthetic 7 alpha-hydroxycholesterol as its diacetate by thin-layer chromatography on alumina. Amounts of 7 alpha-hydroxycholesterol as low as 0.1 nmole could be measured. A comparison of the proposed isotope derivative method with the previously used isotope incorporation method showed that the latter underestimated the enzyme activity by about 20 percent.

Acetylation↗
PubMed1975

Identification of pentahydroxy bile alcohols in cerebrotendinous xanthomatosis: characterization of 5beta-cholestane-3alpha, 7alpha, 12alpha, 24xi, 25-pentol and 5beta-cholestane-3alpha, 7alpha, 12alpha, 23xi, 25-pentol.

This paper describes studies dealing with the nature of the C27 pentahydroxy bile alcohols present in the bile and feces of two patients with cerebrotendinous xanthomatosis (CTX). The presence of a bile alcohol having the structure 5beta-cholestane-3alpha,7alpha,12alpha,24alpha,25-pentol was confirmed by separation of the two 24-hydroxy epimers of 5beta-cholestane-3alpha,7alpha,12alpha,24,25-pentol and characterization of the dpimers by gas-liquid chromatography and infrared and mass spectrometry. Tentative assignment of the 24alpha and 24beta configuration was made on the basis of molecular rotation differences. A second major bile alcohol excreted by the CTX subjects was 5beta-cholestane-3alpha,7alpha,12alpha,23xi,25-pentol. Its structure was determined by infrared spectrometry, proton magnetic resonance spectrometry, and mass spectrometry because a reference compound was not available.

Bile↗
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↗