Biomedical subjects

E H Mosbach

Publications and source records attributed to E H Mosbach.

At least 37 records · Page 2Linked to original sources

PubMed1993

Metabolism of sulfonate analogs of ursodeoxycholic acid and their effects on biliary bile acid composition in hamsters.

The metabolism of sodium 3 alpha,7 beta-dihydroxy-5 beta-cholane-24-sulfonate and sodium 3 alpha,7 beta-dihydroxy-24-nor-5 beta-cholane-23-sulfonate was studied in hamsters. In bile fistula animals these sulfonate analogs of ursodeoxycholic acid were absorbed mainly from the terminal ileum and secreted rapidly into the bile without biotransformation or conjugation. After oral administration, the sulfonate analogs were excreted in the feces at the same rate as chenodeoxycholic acid and its metabolic products. The intestinal microorganisms transformed chenodeoxycholic acid largely into lithocholic acid; the sulfonate analogs were completely resistant to biotransformation. After a 2-week feeding period, the sulfonate analogs of ursodeoxycholic acid accounted for 24.0% and 16.9% of total biliary bile acids. These sulfonates did not affect the proportions of the natural bile acids in the bile, and the ratio of glycine-conjugated bile acids to taurine-conjugated bile acids was not altered by feeding the sulfonates. In contrast, when ursodeoxycholic acid was fed, the proportions of the natural bile acids and the glycine/taurine ratio were changed. These results suggest that the sulfonate analogs had no profound effect on endogenous bile acid metabolism and did not cause a depletion of the hepatic taurine pool during enterohepatic circulation. The sulfonates had no effect on intestinal cholesterol absorption and serum cholesterol levels.

Animals↗

PubMed1992

Palmitic acid enhances cholesterol gallstone incidence in Sasco hamsters fed cholesterol enriched diets.

In an established hamster model of cholesterol cholelithiasis, a semipurified lithogenic diet containing 4% butterfat and 0.3% cholesterol leads to the production of cholesterol gallstones in only 50-60% of animals after a 6-wk feeding period. The purpose of this study was to investigate whether gallstone incidence could be increased while feeding a nutritionally adequate diet of moderate cholesterol content. The semipurified lithogenic diet was modified as follows: (i) substitution of 1.2% palmitic acid for 4% butterfat, and (ii) varying the amount of dietary cholesterol from 0.0 to 0.3% with either butterfat or palmitic acid as the lipid component of the diet. Substitution of palmitic acid for butterfat produced a significantly higher incidence of cholesterol gallstones (94% vs. 53%). Palmitic acid also raised the incidence of gallstones when added to the 0.1% and 0.2% cholesterol diets as compared to butterfat: 0% vs. 44% and 50% vs. 81%, respectively. Gallstone incidence increased from 0% to nearly 100% when the cholesterol content of the palmitic acid diets was raised from 0.0% to 0.3%, indicating a dose response effect with respect to dietary cholesterol. Hamsters fed cholesterol-free diets did not form gallstones. Increased dietary cholesterol led to increased liver weight associated with a significant increase in liver cholesterol concentration. However, the palmitic acid groups had significantly lower liver cholesterol values than the corresponding butterfat groups. Serum and biliary cholesterol concentrations increased with increasing dietary cholesterol intake, but there were no differences between the butterfat and palmitic acid groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Dietary fat and fatty acids modulate cholesterol cholelithiasis in the hamster.

We tested two hypotheses, i) whether the type and the amount of fat in the diet will affect the formation of cholesterol gallstones in the hamsters, and ii) whether palmitic acid, a major fatty acid component of butterfat, can act as a potentiator of cholesterol cholelithiasis in the hamster. Young, male golden Syrian hamsters (Sasco) were fed a semipurified diet containing casein, corn starch, cellulose and cholesterol (0.3%) to which various types and amounts of fat (butterfat, olive oil, menhaden oil, corn oil) were added. All diets contained 2% corn oil to supply essential fatty acids to the growing hamsters. No deaths or illness occurred during the experiment. Animals fed the semipurified diet plus 4% butterfat (group 1) had a gallstone incidence of 63%. Replacement of butterfat with either olive oil, corn oil or menhaden oil prevented the formation of cholesterol gallstones entirely (groups 2-4). When total butterfat was increased from 4% to 8% (group 8), the incidence of cholesterol gallstones increased to 80%. Substitution of 4% olive oil (group 5), corn oil (group 6), or menhaden oil (group 7) for the additional 4% butterfat significantly reduced gallstones to 35%, 45% and 30%, respectively. The replacement of 4% butterfat with 1.2% palmitic acid gave the highest incidence of cholesterol gallstones (95%). These results suggest that butterfat (and one of its components, palmitic acid) intensifies gallstone formation in this model whereas mono- and polyunsaturated fats act as inhibitors of cholesterol cholelithiasis. A fatty acid, possibly palmitic acid, appears to act as lithogen in our model.

Animals↗

PubMed1992

Synthesis of sulfonate analogs of bile acids.

Sulfonate analogs of C23 and C24 bile acids were synthesized from norcholic, norchenodeoxycholic, norursodeoxycholic, nordeoxycholic, norhyodeoxycholic, cholic, deoxycholic, hyodeoxycholic, and lithocholic acids. The principal reactions used were (1) reduction of the bile acids with NaBH4 to the corresponding bile alcohols, (2) selective tosylation of the terminal hydroxyl group, (3) iodination of the tosyl esters with NaI, and (4) treatment of the iodides with Na2SO3 to form the sulfonate analogs of the bile acids. The sulfonate analogs showed polarity similar to that of taurine-conjugated bile acids on thin-layer chromatography. The carbon 13 nuclear magnetic resonance spectral data for the sulfonate analogs were tabulated.

Bile Acids and Salts↗

PubMed1992

Sulfonate analogues of chenodeoxycholic acid: metabolism of sodium 3 alpha, 7 alpha-dihydroxy-25-homo-5 beta-cholane-25-sulfonate and sodium 3 alpha, 7 alpha-dihydroxy-24-nor-5 beta-cholane-23-sulfonate in the hamster.

This report describes the chemical synthesis of a new bile acid analogue, namely, sodium 3 alpha, 7 alpha-dihydroxy-25-homo-5 beta-cholane-25-sulfonate from homochenodeoxycholic acid. The structure of the new compound was assigned by proton magnetic resonance and infrared spectrometry. Its metabolism was studied in the hamster in comparison with sodium 3 alpha, 7 alpha-dihydroxy-24-nor-5 beta-cholane-23-sulfonate and sodium taurochenodeoxycholate. After intraduodenal administration of the 3H-labeled analogues into bile fistula hamsters, both sulfonates were absorbed from the intestine and nearly 80% of the radioactivity was secreted into bile within 8 h. Intra-ileal administration revealed that these compounds resembled taurochenodeoxycholate in that they were much more rapidly absorbed from the ileum than from the proximal small intestine: more than 85% of the radioactivity was recovered in bile within 1 h. After intravenous infusion the sulfonates were efficiently extracted by the liver at rates similar to that of sodium taurochenodeoxycholate. Chromatographic analysis of the bile showed that, regardless of the route of administration, most (> 95%) of the sulfonates were not biotransformed and they became major biliary bile acids. Sodium 3 alpha, 7 alpha-dihydroxy-25-homo-5 beta-cholane-25-sulfonate and, to a lesser extent, sodium 3 alpha, 7 alpha-dihydroxy-24-nor-5 beta-cholane-23-sulfonate induced cholestasis at infusion rates at which sodium taurochenodeoxycholate produced choleresis.

Animals↗

PubMed1991

Replacement of cholesterol gallstones by murideoxycholyl taurine gallstones in prairie dogs fed murideoxycholic acid.

The effect of two hydrophilic bile acids, murideoxycholic acid (3 alpha,6 beta-dihydroxy-5 beta-cholanoic acid) and ursodeoxycholic acid, on cholesterol and bile acid metabolism and hepatic pathology and gallstone composition was studied in the prairie dog. Cholesterol gallstones were induced by feeding a diet containing 1.2% cholesterol for 75 days. The animals were divided into six groups, and gallstone regression was studied as follows: groups 2 and 5, chow plus 0.2% cholesterol; groups 3 and 6, chow plus 0.2% cholesterol plus 0.15% ursodeoxycholic acid; groups 4 and 7, chow plus 0.2% cholesterol plus 0.15% murideoxycholic acid. Animals in groups 2 to 4 were killed after an additional 6 wk; animals in groups 5 to 7 were killed after an additional 12 wk. Gallstone dissolution did not occur in any group. The gallstones in groups 2, 3, 5 and 6 were typical cholesterol aggregates, as determined by polarized light microscopy and Fourier transform infrared spectrometry. The gallstones of the murideoxycholic acid group were large, solitary, dark stones that appeared radiopaque under 22 kVp x-ray examination. Scanning electron microscopy showed that in these stones the cholesterol crystals had been replaced by an amorphous material, both within the stone and on the stone surface. Chemical analysis indicated that at the end of 12 wk the calcium/sodium salt of the taurine conjugate of murideoxycholic acid (murideoxycholyl taurine) comprised 70% of the stones; protein, cholesterol and small amounts of other bile salts were also present. In vitro studies confirmed the insolubility of the sodium and calcium salts of murideoxycholyl taurine. These studies indicate that the hydrophilic bile acids, murideoxycholic acid and ursodeoxycholic acid, did not achieve gallstone dissolution under the conditions used. In the animals fed murideoxycholic acid, an insoluble calcium salt of murideoxycholyl taurine replaced cholesterol as the major constituent of gallbladder stones. This is the first example of an insoluble dihydroxy taurine-conjugated bile acid; administration of the unconjugated bile acid induced precipitation of a kind of gallstone not previously reported. The final result was transformation of cholesterol stones to bile salt stones.

Animals↗

PubMed1991

Aspirin does not inhibit cholesterol cholelithiasis in two established animal models.

The effect of aspirin on cholesterol cholelithiasis was examined in the hamster and the prairie dog. In the prairie dog, diets were composed of semipurified components of chow, plus cholesterol (1.2%), with and without aspirin. Animals were studied for either 2 weeks or 4 weeks. Cholesterol gallstones were present in all groups at the end of each period; aspirin did not alter the incidence of cholelithiasis. All animals studied had cholesterol crystals in the bile when they were killed. Liver cholesterol levels in prairie dogs with and without aspirin tended to be lower in animals fed chow than in animals fed semipurified diets. There were no significant differences in cholesterol levels in the plasma or bile. The cholesterol saturation index of all biles approached unity when animals were fed chow with aspirin; animals fed the semipurified diets had cholesterol saturation indices of less than 1.0. The prairie dogs fed aspirin plus cholesterol in the semipurified diet showed increased levels of biliary chenodeoxycholic acid amidates and concomitant decreased levels of cholic acid amidates compared with animals fed the same diet without aspirin. Hamsters fed aspirin plus cholesterol in a semipurified diet tended to have a greater incidence of gallstones than animals given no aspirin (80% vs. 55%). Liver and bile cholesterol levels were similar with and without aspirin; plasma cholesterol levels increased significantly with aspirin [14.20 vs. 7.80 mmol/L (549 vs. 301 mg/dL)]. Lithogenic indices in all hamsters were above unity; biliary lipids, total lipid concentration, and biliary bile acid composition were similar. These results show that the addition of aspirin to a lithogenic diet does not reduce the incidence of cholelithiasis.

Animals↗

PubMed1991

Metabolism of sodium 3 alpha,7 alpha-dihydroxy-5 beta-cholane-24-sulfonate in hamsters.

Metabolism of sodium 3 alpha,7 alpha-dihydroxy-5 beta-cholane-24-sulfonate, the sulfonate derivative of chenodeoxycholic acid, was studied in hamsters. In bile fistula hamsters, the sulfonate analogue was efficiently absorbed from the ileum and secreted rapidly into the bile without any modification such as conjugation. However, absorption from the jejunum was smaller than that observed for the ileum. After oral administration, the sulfonate analogue of chenodeoxycholic acid was recovered quantitatively in the feces as the unchanged form in contrast to simultaneously administered chenodeoxycholic acid, which was entirely converted to lithocholic acid during its passage through the intestinal tract. These results demonstrate that the sulfonate analogue is absorbed mainly from the ileum by active transport, enters the enterohepatic circulation like the endogenous conjugated bile acids, and completely resists bacterial degradation.

Animals↗

PubMed1991

Chemical synthesis and hepatic biotransformation of 3 alpha,7 alpha-dihydroxy-7 beta-methyl-24-nor-5 beta-cholan-23-oic acid, a 7-methyl derivative of norchenodeoxycholic acid: studies in the hamster.

A new bile acid analogue, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-24-nor-5 beta-cholan-23-oic acid (7-Me-norCDCA) was synthesized from the methyl ester of norursodeoxycholic acid, and its hepatic biotransformation was defined in the hamster. To synthesize 7-Me-norCDCA, the 3 alpha-hydroxyl group of methyl norursodeoxycholate was protected as the hemisuccinate, and the 7 beta-hydroxyl group was oxidized with CrO3 to form the 7-ketone. A Grigard reaction with methyl magnesium iodide followed by alkaline hydrolysis gave 7-Me-norCDCA (greater than 70% yield). The structure of the new compound was confirmed by proton magnetic resonance and mass spectrometry. After intraduodenal administration of the 14C-labeled compound into the anesthetized biliary fistula hamster, it was rapidly and efficiently secreted into the bile; 80% of radioactivity was recovered in 2 h. After intravenous infusion, the compound was efficiently extracted by the liver and secreted into the bile (greater than 75% in 3 h). Most (93%) of the biliary radioactivity was present in biotransformation products. The major biotransformation product (48.7 +/- 6.0%) was a new compound, assigned the structure of 3 alpha,5 beta,7 alpha- trihydroxy-7 beta-methyl-24-nor-5 beta-cholan-23-oic acid (5 beta-hydroxy-7- Me-norCDCA). In addition, conjugates of 7-Me-norCDCA with taurine (13.7 +/- 5.0%), sulfate (10.3 +/- 3.0%), or glucuronide (5.1 +/- 1.7%) were formed. 7-Me-norCDCA was strongly choleretic in the hamster; during its intravenous infusion, bile flow increased 2 to 3 times above the basal level, and the calculated choleretic activity of the compound (and its metabolic products) was much greater than that of many natural bile acids, indicating that the compound induced hypercholeresis. It is concluded that the biotransformation and physiological properties of 7-Me-norCDCA closely resemble those of norCDCA. Based on previous studies, the major biological effect of the 7-methyl group in 7-Me-norCDCA is to prevent its bacterial 7-dehydroxylation in the distal intestine.

Animals↗

PubMed1990

The effect of alfalfa-corn diets on cholesterol metabolism and gallstones in prairie dogs.

Cholesterol gallstones were present in prairie dogs fed alfalfa plus corn with and without exogenous cholesterol (0.4%). The diets fed to the animals for eight weeks contained alfalfa plus corn in fixed proportions of 50:50, 85:15 and 15:85 (w/w). At sacrifice, all animals were healthy but had not gained weight; no deaths occurred during the experiment. Cholesterol gallstones were present in all groups. In the absence of exogenous cholesterol, the highest stone incidence was found in the animals which received the lowest fiber (highest corn) diets (alfalfa plus corn, 50:50, 67%; alfalfa plus corn, 15:85, 83%). Cholesterol gallstone incidence was 100% when exogenous cholesterol was added to the alfalfa plus corn diets (50:50 and 15:85). No pigment gallstones were detected in any animal. Liver and plasma cholesterol concentrations were highest in the animals receiving alfalfa plus corn (15:85) plus 0.4% cholesterol (4.29 mg/g, and 356 mg/dl, respectively). These values were lowest in animals receiving 85% alfalfa plus 15% corn without cholesterol (2.19 mg/g and 88 mg/dl, respectively). Lithogenic indices were below 1.00 in all groups. Biliary bile acids were mainly amidates of cholic acid and chenodeoxycholic acid, with the former predominating. Thus, gallstones can be formed in prairie dogs in the absence of exogenous cholesterol; gallstone incidence is reduced by dietary fiber.

Animals↗

PubMed1990

Bile acids substituted in the 6 position prevent cholesterol gallstone formation in the hamster.

The aim of the present study is to examine the efficacy of 6-hydroxy substituted bile acids on the prevention of cholesterol gallstones in a new hamster model of cholesterol cholelithiasis. Male golden Syrian hamsters were fed a nutritionally adequate semipurified lithogenic diet consisting of casein, cornstarch, soluble starch, butterfat, corn oil, and cellulose plus 0.3% cholesterol. Six different bile acids were added to this diet at the 0.05% level: chenodeoxycholic acid, ursodeoxycholic acid, hyodeoxycholic acid, murideoxycholic acid, 6 beta-methyl-hyodeoxycholic acid, and 6 alpha-methyl-murideoxycholic acid. At the end of the 6-wk feeding period, the control group receiving the lithogenic diet had a 55% incidence of gallstones. It was found that all bile acids had inhibited the formation of cholesterol gallstones; complete prevention of gallstones was observed with all 4 3,6-dihydroxy bile acids, whereas chenodeoxycholic acid and ursodeoxycholic acid were somewhat less effective (80% and 75% prevention, respectively). The accumulation of cholesterol in serum and liver induced by the lithogenic diet was inhibited to some extent by all of the bile acids; hyodeoxycholic acid, murideoxycholic acid, and 6 beta-methyl hyodeoxycholic acid were most effective in this respect. The administered bile acids tended to predominate in bile in the case of chenodeoxycholic acid, hyodeoxycholic acid, and 6 beta-methyl-hyodeoxycholic acid. In contrast, ursodeoxycholic acid seemed to be converted to chenodeoxycholic acid and murideoxycholic acid to hyodeoxycholic acid. Only 4% of the 6-methyl analogue of murideoxycholic acid, 6 alpha-methyl-murideoxycholic acid, was recovered in gallbladder bile. These experiments show that the new hamster model of cholesterol cholelithiasis is suitable for gallstone-prevention studies. It was not possible to draw definite conclusions concerning the mechanism of action of the administered bile acids on the basis of cholesterol saturation or the presence of liquid crystals. The detailed mechanism of gallstone prevention by hydrophilic bile acids in this model remains to be elucidated.

Animals↗

PubMed1990

Metabolism of 7 beta-alkyl chenodeoxycholic acid analogs and their effect on cholesterol metabolism in hamsters.

The metabolism of 7-ethyl- and 7-propyl-chenodeoxycholic acids was studied in hamsters. Both bile acid analogs were absorbed efficiently by the intestine and secreted into the bile at rates similar to those of chenodeoxycholic acid. After intraduodenal administration into bile fistula hamsters, the 7-alkyl analogs were present in bile as the glycine and taurine conjugates. The glycine/taurine ratios were: chenodeoxycholic acid, 1.9; 7-ethyl analog, 0.3; and 7-propyl analog, 0.2. After oral administration, during a 21-day feeding experiment, the 14C-labeled analogs were recovered quantitatively in the feces. Chenodeoxycholic acid was largely 7-dehydroxylated to lithocholic acid in the intestinal tract. In contrast, the 7 alpha-hydroxy group of the 7-alkyl bile acids was completely resistant to bacterial action. 7-Ethyl-chenodeoxycholic acid was transformed in part to a compound tentatively identified as 7 alpha-hydroxy-3-oxo- 7 beta-ethyl-5 beta-cholanoic acid while 7-propyl-chenodeoxycholic acid was excreted unchanged. In the hamsters used, the 7-alkyl bile acid analogs did not inhibit the bacterial dehydroxylation of chenodeoxycholic acid. At the end of the 21-day feeding period, analysis of the gallbladder bile showed that 7-methyl-, 7-ethyl-, and 7-propyl-chenodeoxycholic acids accounted for 38, 31, and 12% of total bile acids, respectively. The 7-alkyl bile acids decreased cholesterol absorption; the 7-propyl analog caused significant decrease in serum and liver cholesterol concentration. These experiments demonstrate that the 7-ethyl- and 7-propyl chenodeoxycholic acids, just like the 7-methyl-analog, are absorbed by the intestine and participate in the enterohepatic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Effects of calcium and bile acid feeding on colon tumors in the rat.

The hypothesis that dietary calcium alters the incidence of colorectal neoplasms was examined in an established model of carcinogenesis. Male Fischer 344 rats (28 days old) were quarantined for 2 weeks. All animals were fed the basal diet (AIN-76) supplemented with cholic acid (0.2%) and/or calcium (1.6%, corresponding to a 3-fold increase above that of the basal diet). N-Methyl-N-nitrosourea (MNU) (2 mg/dose) or saline (control) was given intrarectally to all animals on days 1 and 4 of the experiment. Groups 1-8 were fed the experimental diets concurrently with the first dose of MNU, while groups 9 and 10 were fed the diets 2 weeks prior to MNU (or saline). All animals were sacrificed after 28 weeks. No tumors were observed in the groups given saline (groups 1, 3, 5, 7, and 9). In groups receiving MNU, the addition of cholic acid to the diet (group 4) caused a significant increase in tumors (80% versus 55%), tumors/animal ratio (2.24 versus 0.75), and tumors/tumor-bearing animal ratio (2.80 versus 1.36), group 4 versus group 2, respectively. Increased dietary calcium did not inhibit tumor formation; 68% of animals in groups 6 and 10 had tumors. The combination of dietary cholic acid and calcium (group 8) gave a tumor incidence similar to cholic acid (group 4) alone (72% versus 80%, 2.00 versus 2.24 tumors/animal; 2.77 versus 2.80 tumors/tumor-bearing animal). Most tumors were adenomatous polyps but carcinomas in situ and invasive carcinomas were also present; dietary calcium reduced the number of invasive carcinomas (group 6 versus group 2, P less than 0.04).

Adenocarcinoma↗

PubMed1989

Cholelithiasis in hamsters: effects of cholic acid and calcium on gallstone formation.

Dietary cholic acid (0.1%) and/or calcium (2.6% as calcium carbonate) were added to a semipurified diet containing cholesterol and ethynyl estradiol to determine whether the incidence of pigment and/or cholesterol gallstones would be changed. Male golden Syrian hamsters were fed the experimental diets for 96 days (Group 1, control; Group 3, cholic acid plus calcium) or only an average of 60 days (Group 2, 0.1% cholic acid). Animals in Group 2 became ill (weight loss, low food intake, diarrhea) possibly due to cholic acid (or deoxycholic acid) toxicity. Cholesterol gallstones and crystals were absent in all experimental groups. The incidence of pigment gallstones was: control, Group 1, 12/16; 0.1% cholic acid, Group 2, 3/13; and 0.1% cholic acid plus calcium, Group 3, 11/22. Cholic acid with or without calcium produced an elevation of both liver and plasma cholesterol: Group 2, 80.1 mg/g and 501 mg/dl; Group 3, 103.7 mg/g and 475 mg/dl vs Group 1, 65 mg/g and 209 mg/dl, respectively. The lithogenic indices of the bile were lower in Groups 2 and 3 compared to Group 1, controls, 0.45 and 0.58 vs 1.16, respectively. The extent of the portal tract pathology could not be correlated with the presence or absence of pigment gallstones or with the levels of lithocholic acid in the hamster bile. In summary, when semipurified diets were supplemented with ethynyl estradiol and cholic acid, with and without calcium supplementation, no cholesterol gallstones formed and the incidence of pigment gallstones was not altered.

Animals↗

PubMed1989

Dietary induction of cholesterol gallstones in hamsters from three different sources.

Cholesterol gallstones were produced in young male, golden Syrian hamsters, obtained from three different suppliers, by administering a nutritionally adequate, semipurified diet for periods of either 5 or 10 weeks. The major components of the lithogenic diet were casein, cornstarch, butterfat, corn oil and 0.3% cholesterol. The hamsters were obtained from Sesco, Harlan Sprague-Dawley (Engle hamster) and Charles River (Lakeview hamster). There were profound differences among the three groups with respect to gallstone formation and cholesterol metabolism: The highest incidence of gallstones occurred in Sesco hamsters, 44.4% and 63.6% after 5 and 10 weeks on the lithogenic diet, respectively. In the Engle hamster, after a 5-week feeding, cholesterol crystals and gallstones were absent. When the feeding period was extended to 10 weeks, cholesterol gallstones were present in 45.5% of the animals. In the Lakeview hamsters, neither gallstones nor cholesterol crystals were found in the gallbladder after a 5-week period. After 10 weeks, cholesterol gallstones were found in only a single hamster. In all groups, the lithogenic diet produced large increases of liver, serum and biliary cholesterol concentrations and increased liver weights. When the animals were fed for 5 weeks, only the bile of Sesco hamsters became supersaturated. Supersaturated bile was induced in all groups after a 10-week feeding of the lithogenic diet with cholesterol saturation ranging from 1.47 to 1.97. These data indicate that it is possible to induce cholesterol gallstones in hamsters by means of a nutritionally adequate, semipurified diet of moderate cholesterol content.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

7-Methyl bile acids: effects of chenodeoxycholic acid, cholic acid, and their 7 beta-methyl analogues on the formation of cholesterol gallstones in the prairie dog.

The purpose of this study was to compare the effects of the naturally occurring bile acids (chenodeoxycholic acid and cholic acid) with their 7-methyl analogues (3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid) on gallstone formation and prevention and cholesterol metabolism in the prairie dog. Sixty animals were fed a semipurified diet, containing 0.4% cholesterol, with one of the following acids (0.1%): chenodeoxycholic, cholic, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic, or 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid. This concentration of dietary bile acids amounts to a dose of 27-30 mg/kg.day. After 8 wk, 89% of control animals had gallstones and 94% had cholesterol crystals. Chenodeoxycholic and 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acids decreased the incidence of gallstones to 50%. Cholic acid and 3 alpha,7 alpha,12 alpha-tri-hydroxy-7 beta-methyl-5 beta-cholanoic acid did not prevent gallstone formation. The liver cholesterol level was decreased by chenodeoxycholic acid, whereas cholic and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acids increased serum and liver cholesterol. Each administered bile acid became the predominant biliary bile acid and 7-methyl analogues did not increase secondary bile acids. Fecal analysis of radioactive metabolites using 14C-labeled 7-methyl analogues showed that these compounds are resistant to bacterial 7-dehydroxylation. It was concluded that 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid inhibited gallstone formation as effectively as chenodeoxycholic acid, whereas both cholic and 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acids were not effective. The effects of 7-methyl analogues on the parameters of cholesterol metabolism that we studied were similar to those of their parent compounds, chenodeoxycholic and cholic acids. Thus, 3 alpha,7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid but not 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid offers promise in cholelitholytic therapy for the prevention and possibly dissolution of cholesterol gallstones.

Animals↗

PubMed1989

Synthesis of new bile acid analogues and their metabolism in the hamster: 3 alpha, 6 alpha-dihydroxy-6 beta-methyl-5 beta-cholanoic acid and 3 alpha, 6 beta-dihydroxy-6 alpha-methyl-5 beta-cholanoic acid.

This paper reports the chemical synthesis of two new bile acid analogues, namely, 3 alpha, 6 beta-dihydroxy-6 alpha-methyl-5 beta-cholanoic acid from 3 alpha-hydroxy-6-oxo-5 beta-cholanoic acid and describes their metabolism in the hamster. A Grignard reaction of the oxo acid with methyl magnesium iodide in tetrahydrofuran gave two epimeric dihydroxy-6-methyl-cholanoic acids which were separated as the methyl esters by silica gel column chromatography. The configuration of the 6-methyl groups was assigned by proton nuclear magnetic resonance spectroscopy and was supported by the chromatographic properties of the new compounds. The metabolism of the two new bile acid analogues was studied in the hamster. After intraduodenal administration of the 14C-labeled analogues into bile fistula hamsters, both compounds were absorbed rapidly from the intestine and secreted into bile. Intravenous infusion studies revealed that these compounds were efficiently extracted by the liver; the administered analogues became major biliary bile acids, present as either the glycine or taurine conjugates. These compounds are useful to study the effect of methyl-substituted bile acids on cholesterol and bile acid metabolism and may possibly possess cholelitholytic properties.

Animals↗

PubMed1988

Dissolution of cholesterol gallstones by bile acids in the prairie dog.

The effect of chenodeoxycholic acid, ursodeoxycholic acid and hyodeoxycholic acid on gallstone dissolution was studied in the prairie dog. Cholesterol gallstones were found in all animals after feeding a semipurified diet plus 1.2% cholesterol for six wk. Gallstone regression was examined by feeding a chow diet containing the bile acids (chenodeoxycholic acid, ursodeoxycholic acid or hyodeoxycholic acid) alone (30 mg/kg/day) or in combination (chenodeoxycholic acid plus ursodeoxycholic acid) for an additional six wk. Chenodeoxycholic acid was effective in dissolving established cholesterol gallstones (two out of 16 animals still had stones) and cholesterol crystals (six out of 16 animals had crystals); the hydrophilic bile acids, ursodeoxycholic acid and hyodeoxycholic acid, were ineffective in the six-wk regression study. The lithogenic indices averaged 1.09 at the end of the induction period; all biles became unsaturated with respect to cholesterol after the six-wk regression period (group 1, 0.82; group 2, 0.66; group 3, 0.81; group 4, 0.84; group 5, 0.66). Cholesterol levels in liver, plasma and bile were elevated after the six-wk induction phase (4.59 mg/g, 610 mg/dl and 0.36 mg/ml, respectively) but returned to near normal levels after the six-wk regression period. Biliary bile acids contained increased levels of the dietary bile acid administered to each group. This experiment shows that relatively hydrophobic bile acids may be more effective than hydrophilic bile acids for gallstone dissolution during the period studied.

Animals↗