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Biomedical subjects

E H Mosbach

Publications and source records attributed to E H Mosbach.

156 records · Page 9Linked to original sources
PubMed1968

Experimental cholelithiasis in the rabbit induced by cholestanol feeding: effect of neomycin treatment on bile composition and gallstone formation.

Fed cholestanol is converted by the rabbit to 5alpha-bile acids which coprecipitate with the normally occurring 5beta-bile acids to form gallstones composed of calcium and sodium glycoallodeoxycholate and glycodeoxycholate. The present study shows that oral administration of large doses of neomycin prevents gallstone formation in the cholestanol-fed rabbit and reduces the elevated concentration of allodeoxycholic acid in bile, with a reciprocal increase in allocholic acid concentration. The reduction in the concentration of allodeoxycholic acid and in the incidence of gallstones is proportional to the dose of neomycin; at a concentration of allodeoxycholic acid below about 20% of total bile acids, gallstone formation does not occur. Neomycin probably exerts its action by modifying the anerobic intestinal flora which dehydroxylate allocholic acid to allodeoxycholic acid; if so, this suggests that both hepatic and bacterial transformations are essential steps in the pathogenesis of cholestanol-induced cholelithiasis. The bile of rabbits on a normal diet contains allodeoxycholic acid (5% of total bile acids). A similar decrease in allodeoxycholic acid concentration and reciprocal increase in allocholic acid concentration is observed when neomycin is administered to rabbits on a normal diet.

Animals↗
PubMed1968

7-alpha-hydroxylation of cholestanol by rat liver microsomes.

In a study of the mechanism whereby 5alpha-bile acids are formed from cholestanol, the 7alpha-hydroxylation of cholestanol was investigated in rat liver preparations in vitro. It was found that in the presence of NADPH and oxygen, rat liver microsomes catalyzed the 7alpha-hydroxylation of cholestanol to the same extent as that of cholesterol. The rate of the hydroxylation was enhanced by prior treatment of the experimental rats with cholestyramine (a bile acid sequestrant) or by establishment of bile fistulas-i.e., by partial or complete removal of bile acids from the enterohepatic circulation. The 7-hydroxylation reaction was further stimulated by pretreatment of the animals with phenobarbital, a drug known to produce increased biosynthesis of hepatic endoplasmic membranes. The 7alpha-hydroxylase was inhibited by the reaction product, by sterols with 7-keto or 7beta-hydroxyl groups, and also by mono- and dihydroxy bile acids of the 5beta-series, although cholic acid or taurocholate produced no inhibition unless added in high concentrations. The results of these studies are in accord with the concept that the presence of a Delta(5)-double bond is not required for the enzymatic formation of the 7alpha-hydroxy derivative. The rate of this hydroxylation reaction in vitro appears to depend on the concentration of bile salts in the enterohepatic circulation of the experimental animals from whom the microsomes were obtained.

Animals↗
PubMed1966

Biosynthesis of cholestanol: 5-alpha-cholestan-3-one reductase of rat liver.

The 3-beta-hydroxysteroid dehydrogenase of rat liver which catalyzes the conversion of 5alpha-cholestan-3-one to 5alpha-cholestan-3beta-ol is localized mainly in the microsomal fraction. The enzyme required NADPH as hydrogen donor and differed from the known 3-beta-hydroxysteroid dehydrogenases of the C(19) series in being inactive in the presence of NADH. The microsomal preparations did not reduce the 3-keto groups of cholest-4-en-3-one, cholest-5-en-3-one, or 5beta-cholestan-3-one to the corresponding 3beta-hydroxy compounds. The conversion of 5alpha-cholestan-3-one to 5alpha-cholestan-3beta-ol was only slightly inhibited by the reaction product or by other monohydroxy steroids, but a strong inhibitory effect was noted with cholest-5-en-3-one, 5alpha-cholestane-3beta, 7alpha-diol and 5alpha-cholestan-7-on-3beta-ol. The microsomes, but not high speed supernatant solution, catalyzed the reverse of the cholestanone reductase reaction, namely the conversion of 5alpha-cholestan-3beta-ol to 5alpha-cholestan-3-one in the presence of oxygen and an NADP-generating system. The action of the microsomal preparations upon 5alpha-cholestan-3-one produced 5alpha-cholestan-3alpha-ol in addition to the 3beta-epimer. The 3-alpha-hydroxysteroid dehydrogenase involved functioned with either NADH or NADPH as hydrogen donor. The ratio of 5alpha-cholestan-3beta-ol to 5alpha-cholestan-3alpha-ol formed from 5alpha-cholestan-3-one was approximately 10:1 and was independent of the sex of the animal from which the microsomes were prepared.

Animals↗
PubMedDate not supplied

Effects of chenodeoxycholic and ursodeoxycholic acids on lipid metabolism and gallstone formation in the prairie dog.

The prevention of cholesterol cholelithiasis by dietary chenodeoxycholic and ursodeoxycholic acids was studied in the male prairie dog (Cynomys ludovicianus). Gallstones were induced by administration of a semisynthetic diet containing 0.4% cholesterol for a period of 8 weeks. Groups of 5 or 6 animals received the lithogenic diet with added chenodeoxycholic or ursodeoxycholic acid (0.03% "low dose" or 0.06% "high dose"). Under the conditions used, the incidence of gallstones was reduced with the high dose of chenodeoxycholic acid and the low dose of ursodeoxycholic acid, but cholesterol crystals were detected in the biles of 20 of the 22 animals fed these bile acids. A control group maintained on a low (0.08%) cholesterol semisynthetic diet exhibited neither crystals nor stones and was the only group with a lithogenic index below 1.0. The administered bile acids tended to reduce the accumulation of cholesterol in liver and plasma. The activity of hepatic HMG-CoA reductase was significantly inhibited with all cholesterol-supplemented diets. Cholesterol 7 alpha-hydroxylase activity was elevated 83% in prairie dogs fed 0.4% cholesterol, but tended to return to normal levels when bile acids were added to this diet. Histologically, the livers of all animals on the semisynthetic (cholesterol-supplemented) diet exhibited bile duct proliferation, as well as portal fibrosis and inflammatory infiltration. These morphologic alterations were ameliorated by low dose supplementation with either chenodeoxycholic or ursodeoxycholic acid, but high dose bile acid supplementation failed to reduce these pathologic changes.

Animals↗
PubMedDate not supplied

Gallstone prevention in prairie dogs: comparison of chow vs. semisynthetic diets.

The effects of a standard rodent chow were compared with those of a semisynthetic diet of known composition (with and without added cholesterol) in the prairie dog model of cholesterol cholelithiasis. Gallstone incidence was 40% higher in animals fed a semisynthetic diet plus cholesterol compared to chow plus cholesterol. The semisynthetic diet plus cholesterol caused significant increases in tissue cholesterol levels (serum, liver and bile) and lithogenic index, but significant decreases in the activity of hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and cholesterol 7 alpha-hydroxylase compared to chow plus cholesterol. Histologic study of liver sections revealed that the semisynthetic diet plus cholesterol resulted in moderate to marked portal tract changes characterized by bile duct proliferation, inflammatory infiltration and fibrosis, whereas the cholesterol-supplemented chow diet caused only slight bile duct proliferation with minimal inflammation and fibrosis in the portal areas. Dietary hyodeoxycholic acid prevented cholesterol gallstones and biliary cholesterol crystals when added to either chow plus cholesterol or semisynthetic plus cholesterol diets. The hyodeoxycholic acid supplements also prevented the development of severe histopathologic alterations along the portal tracts. Biliary cholesterol levels were elevated in prairie dogs fed cholesterol plus hyodeoxycholic acid; these animals had liquid crystals in the bile, and hyodeoxycholic acid and its 6 beta-isomer became the major biliary bile acids. A semisynthetic diet plus cholesterol is superior to a high cholesterol chow diet for gallstone formation and prevention studies, but in prolonged feeding experiments, the potential hepatotoxicity of this diet in the prairie dog must be appreciated.

Animal Nutritional Physiological Phenomena↗
PubMedDate not supplied

Comparative effects of deoxycholate and 7-methyl-deoxycholate in the hamster.

The metabolism and effect on biliary lipids of a new bile acid analog, 7-methyl-deoxycholic acid, were studied and compared with those of deoxycholic acid in the hamster. 14C-Labeled 7-methyl-deoxycholic acid and deoxycholic acid were administered intravenously or intraduodenally to bile fistula hamsters at 1.0 or 4.0 mumoles per min X kg, and hepatic bile was analyzed for radioactive metabolites and biliary lipid outputs. Deoxycholic acid and 7-methyl-deoxycholic acid were efficiently absorbed from the intestine, extracted by the liver and excreted into bile as taurine and glycine conjugates. Twenty per cent of deoxycholic acid was 7 alpha-hydroxylated to cholic acid while 7-methyl-deoxycholic acid did not undergo hydroxylation. During deoxycholic acid infusion, the biliary secretion of phospholipid did not increase, and the bile became more lithogenic. In contrast, 7-methyl-deoxycholic acid stimulated phospholipid secretion, and bile became less lithogenic. Although pathologic changes in the liver were inconstant and mostly mild, both bile acids were toxic in the hamster; hemolysis and death due to respiratory distress were observed.

Animals↗
PubMedDate not supplied

Synthesis of bile acid analogs: 7-alkylated chenodeoxycholic acids.

This paper describes a method for the preparation of 7-alkylated chenodeoxycholic acids from 3 alpha-hydroxy-7-oxo-5 beta-cholanoic acid. The synthetic procedure is based upon a Grignard reaction between the keto bile acid and an alkyl magnesium halide. Under the conditions employed, the introduction of alkyl groups is highly stereoselective. Only 7 beta-alkylated epimers are obtained. The overall yield is several-fold higher than that obtained by the previous method, which involved the preparation of an oxazoline intermediate.

Bile Acids and Salts↗