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1.
J H Iser Paul N Maton Gerard M Murphy R Hermon Dowling 《BMJ (Clinical research ed.)》1978,1(6126):1509-1512
In most patients with radiolucent gall stones who were given chenodeoxycholic acid (CDCA) in doses of 13-15 mg/kg body weight/day the bile became unsaturated in cholesterol, and their gall stones dissolved. The patients whose stones did not dissolve were significantly heavier and fatter than the responders, which suggested that obese patients might be “resistant” to the effects of CDCA. To test this hypothesis, 32 consecutive patients presenting for medical treatment of gall stones had their ideal body weight (IBW) and estimated body fat mass calculated. The eight most obese and the eight least obese patients were then selected, and their fasting bile lipid responses to CDCA 13-15 mg/kg/day were measured. The very obese patients were also given larger doses, and any changes in bile lipid composition were studied in relation to subsequent gall-stone dissolution.Before treatment the obese patients had a higher mean biliary cholesterol saturation index than the non-obese patients, and this difference was maintained during treatment with the normal dose of CDCA: the bile in the obese patients remained supersaturated while that in the non-obese became unsaturated with cholesterol. When the obese patients were given larger doses of CDCA their bile ultimately became unsaturated in cholesterol. Gall stones dissolved partially or completely in five of the eight non-obese patients after 6-18 months of 13-15 mg CDCA/kg/day, but none of the obese patients showed any response after comparable periods of treatment with this standard dose. With increased doses and unsaturated bile, however, three of the obese patients showed partial gall-stone dissolution after 3-12 months'' treatment and one showed complete gall-stone dissolution after three years'' treatment.These results suggest that when giving CDCA to patients with gall stones, larger than normal doses (some 18-20 mg/kg/day) should be prescribed. Alternatively the lipid composition of the patients'' bile should be monitored by duodenal intubation and the CDCA dose increased until the bile becomes unsaturated in cholesterol. 相似文献
2.
《Biocatalysis and Biotransformation》2013,31(2):119-132
Several hydrolases have been employed for the resolution, carried out both in aqueous and organic media, of compounds of pharmaceutical interest. Among these are the mucolytic drug trans-sobrerol, the precursors of (R)- and (S)-broxaterol (a β-adrenergic stimulant), of (R)- and (S)-cycloserine and of (+)- and (-)-desoxymuscarine, and several 2-cyclohexen-l-ols (building blocks for the synthesis of eburnane alkaloids) and bicyclic isoxazolines (building blocks for aminosugars, antibiotics and β-hydroxyacids). The regioselective acylation of chloramphenicol and bile acids has also been achieved by lipases. Hydroxysteroid dehydrogenases have been used to carry out the selective oxidoreduction of both steroidic and non-steroidic compounds. For example, precursors of chenodeoxycholic acid and ursodeoxycholic acid, drugs widely employed for the dissolution of cholesterol gall stones, have been prepared in high yield and purity in membrane reactors with NAD(P)(H) regeneration. The precursors of the eight stereoisomers of muscarine have also been prepared with the same enzymes. 相似文献
3.
I A MacDonald C N Williams J D Sutherland A C MacDonald 《Analytical biochemistry》1983,135(2):349-354
Ursodeoxycholic acid was estimated in bile samples from humans and wild North American black bears using 7 beta-hydroxysteroid dehydrogenase purified from Clostridium absonum by Procion Red affinity chromatography. The percentage ursodeoxycholic acid was calculated by two methods: (a) 7 beta-hydroxyl groups were quantified using 7 beta-hydroxysteroid dehydrogenase and 3 alpha-hydroxyl groups (total bile acids) were quantified using 3 alpha-hydroxysteroid dehydrogenase. The percentage ursodeoxycholic acid was calculated on the basis of [7 beta-hydroxyl groups]/[3 alpha-hydroxyl groups] X 100. (b) Bile was hydrolyzed with sodium hydroxide and subjected to thin-layer chromatography. Bands corresponding to cholic acid, chenodeoxycholic acid plus deoxycholic acid, and ursodeoxycholic acid were identified by the use of standards and Komarowsky's spray reagent. Total bile acids and total ursodeoxycholic acid were measured by elution of silica gel in unsprayed areas corresponding to the bile acid standards and quantification of the total bile acid in each eluate. Direct comparison of these methods validated the use of 7 beta-hydroxysteroid dehydrogenase in the estimation of ursodeoxycholic acid in the biles of black bears and of patients fed ursodeoxycholic acid for cholesterol gallstone dissolution. Relative percentages of ursodeoxycholic acid were 8-24% in four bears and 22 and 27% in the patients ingesting 500 and 750 mg ursodeoxycholic acid per day for 3 months, respectively. Predictably lower values were obtained in two control subjects and one patient ingesting 750 mg chenodeoxycholic acid per day for 3 months. 相似文献
4.
Thirty patients with radiolucent stones in a radiologically functioning gall bladder were treated for up to two years with a combination of Rowachol (one capsule twice daily), a mixture of cyclic monoterpenes, and chenodeoxycholic acid (7.0-10.5 mg/kg/day). The patients were not selected for body weight or size of stones. All complete dissolutions diagnosed by oral cholecystography were confirmed or refuted by ultrasound examination. Control of symptoms was excellent, only one patient withdrawing from the study because of persistent biliary pain. No evidence of hepatotoxicity was detected biochemically, and diarrhoea due to chenodeoxycholic acid was minimal at this dose. Stones disappeared completely in 11 patients (37%) within one year and in 15 (50%) within two years. These results compared favourably with those obtained with similar doses of chenodeoxycholic acid alone, in particular those of the National Co-operative Gallstone Study (complete dissolution in 13.5% of patients at two years). Treatment with a combination of medium dose chenodeoxycholic acid with Rowachol for radiolucent gall stones is economical, effective, and likely to minimise persistent symptoms and adverse effects of treatment. 相似文献
5.
G S Tint G R Xu A K Batta S Shefer W Niemann G Salen 《Journal of lipid research》1990,31(7):1301-1306
Guinea pig gallbladder bile contains chenodeoxycholic acid (62 +/- 5%), ursodeoxycholic acid (8 +/- 5%), and 7-ketolithocholic acid (30 +/- 5%). All three bile acids became labeled to the same specific activity within 30 min after [3H]cholesterol was injected into bile fistula guinea pigs. When a mixture of [3H]ursodeoxycholic acid and [14C]chenodeoxycholic acid was infused into another bile fistula guinea pig, little 3H could be detected in either chenodeoxycholic acid or 7-ketolithocholic acid. But, 14C was efficiently incorporated into ursodeoxycholic and 7-ketolithocholic acids. Monohydroxylated bile acids make up 51% and ursodeoxycholic acid 38% of fecal bile acids. After 3 weeks of antibiotic therapy, lithocholic acid was reduced to 6% of the total, but ursodeoxycholic acid (5-11%) and 7-ketolithocholic (15-21%) acid persisted in bile. Lathosterol constituted 19% of skin sterols and was detected in the feces of an antibiotic-fed animal. After one bile fistula guinea pig suffered a partial biliary obstruction, ursodeoxycholic and 7-ketolithocholic acids increased to 46% and 22% of total bile acids, respectively. These results demonstrate that chenodeoxycholic acid, ursodeoxycholic acid, and 7-ketolithocholic acid can all be made in the liver of the guinea pig. 相似文献
6.
Hirotsune Igimi Noriyuki Tamesue Yuichi Ikejiri Hidehiko Shimura 《Life sciences》1977,21(9):1373-1379
In vitro solubilization of cholesterol by sodium ursodeoxycholate was low in bile salt alone system. In the bile salt-lecithin system, the cholesterol solubilization was increased to a considerable extent but remained much lower than that induced by chenodeoxycholic acid. Oral treatment with ursodeoxycholic acid in patients without evidence of hepatobiliary diseases caused a marked increase of ursodeoxycholate in gallbladder-bile, but a little change in the content of other bile salts. These results suggest that oral treatment with ursodeoxycholic acid should be much inferior to treatment with chenodeoxycholic acid. 相似文献
7.
Increased (23R)-hydroxylase activity in patients suffering from cerebrotendinous xanthomatosis, resulting in (23R)-hydroxylation of bile acids 总被引:1,自引:0,他引:1
B J Koopman B G Wolthers J C Van der Molen G T Nagel H Rutgers B Strijtveen B Kaptein 《Biochimica et biophysica acta》1986,883(3):585-592
Patients suffering from cerebrotendinous xanthomatosis, an inborn error of metabolism in bile acid synthesis, excrete excessive amounts of 23-hydroxylated bile alcohols, 23-norcholic acid and 23-hydroxycholic acid into urine. In this study the configuration of this excreted 23-hydroxycholic acid was established as (23R)-hydroxycholic acid. Urine samples of two treated patients, receiving chenodeoxycholic acid, were investigated to see whether this administered bile acid was partly converted into 23-hydroxychenodeoxycholic acid. One patient was treated with ursodeoxycholic acid for 1 month and subsequently with chenodeoxycholic acid, and the urinary excretion of both (23R)-hydroxychenodeoxycholic acid and (23R)-hydroxyursodeoxycholic acid were followed. Indeed, all three patients excreted (23R)-hydroxylated chenodeoxycholic acid during oral treatment with chenodeoxycholic acid, and the patient treated with ursodeoxycholic acid excreted (23R)-hydroxylated ursodeoxycholic acid. During treatment with chenodeoxycholic acid the excretion of (23R)-hydroxychenodeoxycholic acid increases at first and later on decreases markedly. These findings suggest increased (23R)-hydroxylase activity in patients suffering from cerebrotendinous xanthomatosis, acting both on endogenously synthesized bile alcohols and on exogenously administered bile acids; during continuation of chenodeoxycholic acid treatment in an effective dose (750 mg/day) this enzyme activity gradually disappears. 相似文献
8.
Hypercholesterolaemia has been predicted as a possible complication of chenodeoxycholic acid treatment for gall stones. To exclude this, fasting serum lipids were measured in patients with stones before and at monthly intervals for six months after starting chenodeoxycholic acid. Before treatment half of a group of 36 patients with presumed cholesterol gall stones had serum cholesterol levels exceeding 260 mg/100 ml or serum triglyceride values greater than 160 mg/100 ml or both; these lipid levels were significantly greater than those in control subjects matched for age and sex. Treatment with chenodeoxycholic acid (0·5-1·5 g/day by mouth) did not change serum cholesterol levels but did significantly reduce serum triglyceride concentrations from a pretreatment level of 118 (± S.E. of mean 11·7) mg/100 ml to 95 (± 7·2) mg/100 ml after six months of therapy. The mechanism of this triglyceride-lowering action of chenodeoxycholic acid is not known, but it may have therapeutic value in patients with hypertriglyceridaemia. 相似文献
9.
Synthesis of the alpha,beta-unsaturated analogues of cholic acid, deoxycholic acid, chenodeoxycholic acid, and ursodeoxycholic acid is described. Each common bile acid was converted to the corresponding C22 aldehyde which was then converted to the delta 22 bile acid by Wittig reaction with methyl (triphenylphosphoranylidene)acetate. The synthetic unsaturated bile acids were characterized by thin-layer chromatography, gas-liquid chromatography, and mass spectrometry. 相似文献
10.
Leslie J. Schoenfield Leonard I. Goldstein Joel Panish J. Manny Shore 《The Western journal of medicine》1976,124(4):299-315
Cholesterol saturation of bile has a primary role in the pathogenesis of gallstone formation. Predisposing factors should be considered. The characteristic features of biliary colic are important to keep in mind, as well as the fact that a history of fatty food intolerance is not of value in the diagnosis of gallstones. The technique of endoscopic retrograde cholangiography is useful for the diagnosis of bile duct stones in jaundiced patients and in patients with a strong clinical history, but in whom findings on oral and intravenous cholangiograms are within normal limits. Improved techniques of operative cholangiography to diminish the incidence of retained gallstones have been developed. Also, choledochoscopy provides a remarkable technique for diagnosis and choledocholithotomy. The dissolution of gallstones with chenodeoxycholic acid is an experimental procedure. This bile acid is thought to act by increasing the chenodeoxycholic acid pool size and decreasing cholesterol synthesis and secretion, thereby reversing the defects responsible for gallstone formation. 相似文献
11.
I A MacDonald Y P Rochon D M Hutchison L V Holdeman 《Applied and environmental microbiology》1982,44(5):1187-1195
A gram-positive, anaerobic, chain-forming, rod-shaped anaerobe (isolate G20-7) was isolated from normal human feces. This organism was identified by cellular morphology as well as fermentative and biochemical data as Eubacterium aerofaciens. When isolate G20-7 was grown in the presence of Bacteroides fragilis or Escherichia coli (or another 7 alpha-hydroxysteroid dehydrogenase producer) and chenodeoxycholic acid, ursodeoxycholic acid produced. Time course curves revealed that 3 alpha-hydroxy-7-keto-5 beta-cholanoic acid produced by B. fragilis or E. coli or introduced into the medium as a pure substance was reduced by G20-7 specifically to ursodeoxycholic acid. The addition of glycine- and taurine-conjugated primary bile acids (chenodeoxycholic and cholic acids) and other bile acids to binary cultures of B. fragilis and G20-7 revealed that (i) both conjugates were hydrolyzed to give free bile acids, (ii) ursocholic acid (3 alpha, 7 beta, 12 alpha-trihydroxy-5 beta-cholanoic acid) was produced when conjugated (or free) cholic acid was the substrate, and (iii) the epimerization reaction was at least partially reversible. Corroborating these observations, an NADP-dependent 7 beta-hydroxysteroid dehydrogenase (reacting specifically with 7 beta-OH-groups) was demonstrated in cell-free preparations of isolate G20-7; production of the enzyme was optimal at between 12 and 18 h of growth. This enzyme, when measured in the oxidative direction, was active with ursodeoxycholic acid, ursocholic acid, and the taurine conjugate of ursodeoxycholic acid (but not with chenodeoxycholic, deoxycholic, or cholic acids) and displayed an optimal pH range of 9.8 to 10.2 相似文献
12.
Formation of ursodeoxycholic acid from chenodeoxycholic acid by a 7 beta-hydroxysteroid dehydrogenase-elaborating Eubacterium aerofaciens strain cocultured with 7 alpha-hydroxysteroid dehydrogenase-elaborating organisms. 总被引:4,自引:3,他引:1
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A gram-positive, anaerobic, chain-forming, rod-shaped anaerobe (isolate G20-7) was isolated from normal human feces. This organism was identified by cellular morphology as well as fermentative and biochemical data as Eubacterium aerofaciens. When isolate G20-7 was grown in the presence of Bacteroides fragilis or Escherichia coli (or another 7 alpha-hydroxysteroid dehydrogenase producer) and chenodeoxycholic acid, ursodeoxycholic acid produced. Time course curves revealed that 3 alpha-hydroxy-7-keto-5 beta-cholanoic acid produced by B. fragilis or E. coli or introduced into the medium as a pure substance was reduced by G20-7 specifically to ursodeoxycholic acid. The addition of glycine- and taurine-conjugated primary bile acids (chenodeoxycholic and cholic acids) and other bile acids to binary cultures of B. fragilis and G20-7 revealed that (i) both conjugates were hydrolyzed to give free bile acids, (ii) ursocholic acid (3 alpha, 7 beta, 12 alpha-trihydroxy-5 beta-cholanoic acid) was produced when conjugated (or free) cholic acid was the substrate, and (iii) the epimerization reaction was at least partially reversible. Corroborating these observations, an NADP-dependent 7 beta-hydroxysteroid dehydrogenase (reacting specifically with 7 beta-OH-groups) was demonstrated in cell-free preparations of isolate G20-7; production of the enzyme was optimal at between 12 and 18 h of growth. This enzyme, when measured in the oxidative direction, was active with ursodeoxycholic acid, ursocholic acid, and the taurine conjugate of ursodeoxycholic acid (but not with chenodeoxycholic, deoxycholic, or cholic acids) and displayed an optimal pH range of 9.8 to 10.2 相似文献
13.
A K Batta R Arora G Salen G S Tint D Eskreis S Katz 《Journal of lipid research》1989,30(12):1953-1962
We have studied the effect of ursodeoxycholic acid on the serum and urinary bile acids in seven patients with moderate to severe primary biliary cirrhosis. Bile acids were characterized by gas-liquid chromatography-mass spectrometry and quantified by capillary gas-liquid chromatography. Serum bile acids were elevated 26-fold over control values, with 2.2 times more cholic acid than chenodeoxycholic acid. Urinary bile acid output was elevated 22-fold over control values with a cholic acid:chenodeoxycholic acid ratio of 1.6. In addition, lithocholic acid, deoxycholic acid, ursodeoxycholic acid, 1 beta-hydroxycholic acid, 1 beta-hydroxydeoxycholic acid, and hyocholic acid were identified in both serum and urine; the proportions of the 1- and 6-hydroxylated bile acids were much higher in urine than in serum of the patients (32.1% versus 4.2%). Three months of placebo administration did not change the serum and urinary bile acid composition. In contrast, ursodeoxycholic acid feeding (12-15 mg/kg body weight per day) for 6 months resulted in a 25% decline in the total serum bile acid concentration from the pretreatment values. The proportion of ursodeoxycholic acid increased from 2.1 to 41.2% of total bile acids, so that total fasting serum endogenous bile acid levels decreased 62.4%. Ursodeoxycholic acid feeding substantially increased urinary bile acid output, with ursodeoxycholic acid comprising 58.1%. The proportion of 1- and 6- hydroxylated endogenous bile acids was reduced by 45.5% from pretreatment levels and approximately 4.5% of the urinary bile acids were omega-muricholic acid, 1 beta-hydroxyursodeoxycholic acid, and 21-hydroxyursodeoxycholic acid. These results demonstrate significant changes in the serum and urinary bile acid pattern in primary biliary cirrhosis during ursodeoxycholic acid treatment. The beneficial effect of ursodeoxycholic acid may be due to reduction of the hydroxylated derivatives of endogenous bile acids together with the appearance of hydroxylated derivatives of ursodeoxycholic acid or it may be due to displacement of the more hydrophobic endogenous bile acids by the hydrophilic ursodeoxycholic acid. 相似文献
14.
Fifteen patients with gall stones who were taking chenodeoxycholic acid(CDCA) 15 mg/kg at bedtime participated in two separate experiments to investigate the effects of altering sterol intake on the cholesterol saturation index (SI) of fasting gall-bladder bile. In experiment I the 15 patients on an unrestricted diet had a SI of 0.87 +/- 0.04 (mean +/- SE of mean), which fell to 0.75 +/- 0.04 after one week in hospital on a diet of 100 mg cholesterol daily. In experiment II seven of the patients were given four different dietary regimens lasting one month each in random order as outpatients. On a diet of 600 mg of cholesterol daily the mean SI was 0.72 +/- 0.05, which fell to 0.67 +/- 0.05 when the patients were put on a 100 mg cholesterol diet. The addition of plant sterols (3 g daily) to both diets raised the mean SIs to 0.80 +/- 0.05 and 0.77 +/- 0.05 respectively. The percentage CDCA in bile was unaffected by alterations in the cholesterol and plant sterol intakes. We conclude that a low-cholesterol diet but not a high intake of plant sterols enhances the effect of CDCA in patients with gall stones. 相似文献
15.
C J O'Connor R G Wallace K Iwamoto T Taguchi J Sunamoto 《Biochimica et biophysica acta》1985,817(1):95-102
Physiochemical damage of egg phosphatidylcholine liposomes, caused by the salts of three bile acids, chenodeoxycholic acid, ursodeoxycholic acid, and cholic acid, has been investigated. Of the three bile salts, that of chenodeoxycholic acid was the most destructive, and the effect of the damage was examined by monitoring the induced 6-carboxyfluorescein release from the liposomes. For all three of the bile salts and under the experimental conditions, the minimum (effective) concentrations causing the 6-carboxyfluorescein release were below their critical micelle concentrations. In the case of the salt of chenodeoxycholic acid, the presence of cholesterol in the liposomal bilayers did not show any significant effect on the induced 6-carboxyfluorescein release, while, for the salts of ursodeoxycholic acid and cholic acid, the presence of cholesterol tended to depress the release. Permeation of bile salts into the membranes of liposomal bilayers made these membranes more fluid, and this fluidity was monitored by measuring the change in fluorescence polarization using 1,6-diphenylhexatriene entrapped in the liposomes. Coating the liposomes with polysaccharides, to make them more hydrophobic, led to their easier lysis by the bile salts. 相似文献
16.
Cholic acid, deoxycholic acid, chenodeoxycholic acid, and ursodeoxycholic acid were purified by a foam fractionation method. Using thermogravimetric analysis, the attached water molecule was found to be completely removed from solids of the latter three at 100 degrees C, while cholic acid still had one water molecule of crystallization per two cholic acid molecules at that temperature. The acidity constants of the acids were accurately determined from aqueous solubility measurements at different pH values and at 15, 25, 35, and 45 degrees C. The enthalpy change of dissolution from temperature dependence of solubility as undissociated acid monomer was much less than those of common ionic surfactants. This results from a smaller entropy increase on dissolution due to the hardly flexible hydrophobic structure of these bile acids. 相似文献
17.
Gall bladder and hepatic bile was sampled from 66 patients undergoing elective operations on the biliary tract. Fifty-one patients had cholesterol gall stones but only 59% of these were found to have bile which was supersaturated with cholesterol. Repeated sampling of hepatic bile from patients with T-tubes showed that the secretion of supersaturated bile was intermittent.These results indicate that it is impossible to separate patients with cholesterol stones from controls simply by examination of the lipid composition of their bile, since an appreciable number of bile samples from patients with cholesterol stones were unsaturated.The fact that cholesterol gall stones form when the bile is supersaturated with cholesterol only intermittently suggests that the gall bladder may also have a part in their formation. 相似文献
18.
The mutagenicity of bile acids using a fluctuation test 总被引:1,自引:0,他引:1
The mutagenicity of bile acids was detected by a fluctuation test using Salmonella typhimurium TA100 and TA98 as tester strains. Cholic acid, chenodeoxycholic acid, deoxycholic acid and ursodeoxycholic acid were mutagenic in this test while lithocholic acid was not. The mutagenicity of the bile acids on a molar basis was roughly one-fourth that of methyl methanesulfonate, a moderately potent mutagen. Epidemiological studies have shown a high correlation between levels of bile acids excreted and colon cancer. However, no evidence has previously been reported showing that bile acids are mutagenic. Our results suggest that bile acids may be important in the etiology of colon cancer. 相似文献
19.
The effects of cholestyramine feeding on biliary ursodeoxycholic acid, fecal excretion of bile acids and neutral sterols on cholesterol 7α-hydroxylase and hepatic HMG-CoA reductase were examined in the guinea pig. In the bile there was a 57% decrease in the concentration of ursodeoxycholic acid while an increase was observed in the concentration of chenodeoxycholic acid. Cholestyramine feeding for ten days resulted in a decrease in plasma cholesterol levels and an increase in both hepatic HMG-CoA reductase and cholesterol 7α-hydroxylase activities. The fecal excretion of both bile acids and neutral sterols was significantly increased. 相似文献
20.
《Comparative biochemistry and physiology. A, Comparative physiology》1978,59(4):653-659
- 1.1. Bile production decreased after bile diversion, but increased when bile was returned to the duodenum, and during i.v. infusion of chenodeoxycholic and of taurocholic acid. In chickens, unlike rabbits, rats and guinea pigs, only a small fraction of bile flow was apparently independent of bile salt secretion.
- 2.2. The flow of bile and pancreatic juice increased when chickens were fed, but did not change after i.v. porcine secretin. Infusion of acid to the duodenum had no effect on bile flow, but pancreatic juice flow increased.
- 3.3. Feeding was not associated with any secretin-like response in bile flow in chickens, and the increases in bile flow which occurred after feeding were attributed to contraction of the gall bladder.