Polymorphism of chenodeoxycholic acid.
Polymorphism of chenodeoxycholic acid was studied by differential thermal analysis and X-ray diffraction. Four polymorphic forms (three crystalline and one amorphous) were characterized.
Chenodeoxycholic Acid↗
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Importance of peroxisomes in the formation of chenodeoxycholic acid in human liver. Metabolism of 3 alpha,7 alpha-dihydroxy-5 beta-cholestanoic acid in Zellweger syndrome.
Infantile Zellweger syndrome belongs to the group of peroxisomal disorders that lack peroxisomes. Both trihydroxycoprostanic acid (THCA), the precursor to cholic acid, and dihydroxycoprostanic acid (DHCA), the precursor to chenodeoxycholic acid, accumulate in this disease. In previous studies, we have shown that liver peroxisomes are required for the conversion of THCA into cholic acid both in vitro and in vivo by measuring a defective conversion in infants with Zellweger syndrome. In our present study, the conversion of DHCA into chenodeoxycholic acid has been measured in an infant with Zellweger syndrome to evaluate the importance of liver peroxisomes for the formation of chenodeoxycholic acid. Coprostanic acidemia was present from the second day of life with high levels of THCA and only trace amounts of DHCA. The conversion of i.v. administered [3H]DHCA into chenodeoxycholic acid was only 7% compared with the 80% conversion in an analogous study in an adult. There was, however, a rapid incorporation of 3H into biliary THCA and, after a lag phase, the 3H was incorporated into biliary cholic acid. After 72 h, 15% of [3H]DHCA was converted to cholic acid. The pool size of DHCA was 1.2 mg/m2 and the pool size of both cholic acid and chenodeoxycholic acid was markedly reduced. The renal excretion of cholic acid was more efficient than that of the less polar chenodeoxycholic acid. More polar metabolites of DHCA and THCA are formed in alternative metabolic pathways facilitating renal excretion of these toxic intermediates. We conclude that liver peroxisomes are essential for a normal conversion of DHCA into chenodeoxycholic acid.
Bile↗
[Metabolism of bile acids. III. Metabolism of chenodeoxycholic acid (author's transl)].
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Animals↗
Metabolism of bile acids. VI. Metabolism of chenodeoxycholic acid in female rats.
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Administration, Oral↗
Formation of chenodeoxycholic acid from 3 alpha, 7 alpha-dihydroxy-5 beta-cholestanoic acid by rat liver peroxisomes.
The oxidation of the side chain of 3 alpha, 7 alpha-dihydroxy-5 beta-cholestanoic acid (DHCA) into chenodeoxycholic acid has been studied in subcellular fractions of rat liver. The product was separated from the substrate by high pressure liquid chromatography and identified by gas-liquid chromatography-mass spectrometry. The highest specific rate of conversion was found in the heavy (M) and the light (L) mitochondrial fractions with the highest enrichment in the L fraction. Washing the M fraction reduced the side chain cleavage activity by 90%. The peroxisomal marker enzyme urate oxidase was reduced to the same extent. The activity found in the M fraction may thus be due to peroxisomal contamination. After centrifugation of the L fraction on a Nycodenz density gradient, the highest specific activity for side chain cleavage of DHCA (31 nmol X mg-1 X h-1) was found in the fraction with the highest peroxisomal marker enzyme activity. This fraction also catalyzed conversion of 3 alpha,7 alpha,12 alpha-5 beta-cholestanoic acid (THCA) into cholic acid at the highest rate (32 nmol X mg-1 X h-1). The peroxisomal oxidation of DHCA into chenodeoxycholic acid required the presence of ATP, CoA, Mg2+, and NAD in the incubation medium. The reaction was not inhibited by KCN. It is concluded that rat liver peroxisomes contain enzymes able to catalyze the cleavage of the side chain of both DHCA and THCA. The enzymes involved are similar to, but not necessarily identical to, those involved in the peroxisomal beta-oxidation of fatty acids.
Animals↗
The effect of chenodeoxycholic acid feeding on bile acid kinetics and fecal neutral steroid excretion in patients with hyperlipoproteinemia types II and IV.
The kinetics of 24-14C-cholic acid and 3H-chenodeoxycholic acid and the elimination of cholesterol as fecal neutral steroids were studied in 6 patients with Type II and 7 patients with Type IV lipoprotein pattern before and during the ingestion of 0.8 to 1.0 Gm. of chenodeoxycholic acid per day. During treatment, the pool size of chenodeoxycholic acid increased in all subjects (not studied in one Type IV patient). In Type II patients, this effect was associated with a decrease of the cholic acid pool size from 868 +/- 141 to 213 +/- 51 mg. and of the cholic acid synthesis from 204 +/- 36 to 54 +/- 20 mg. per day. In the patients with hyperlopoproteinemia Type IV, the cholic acid pool size diminished in 6 of the 7 subjects all of whom showed a decrease in the cholic acid synthesis on the average from 607 +/- 155 to 202 +/- 44 mg. per day. It is suggested that the feedback control of cholic acid synthesis is less sensitive in the Type IV than in the Type II patients. Chenodeoxycholic acid feeding did not influence the fecal excretion of cholesterol, coprostanol, and coprostanone in a consistent way.
Adult↗
Transport of chenodeoxycholic acid and its 3-alpha- and 7-alpha-sulfates by isolated perfused rat liver.
In patients with cholestasis, levels of sulfated bile acids rise. Sulfate esters of chenodeoxycholic acid are the most abundant of these bile acid sulfates. These compounds are taken up by the liver and excreted into bile, although their plasma clearance and biliary excretion are reduced compared with that of unsulfated bile acids. It is not clear whether this is due to differences in intrinsic hepatic uptake or biliary excretion. In the present study, single-pass transport kinetics of chenodeoxycholic acid 3-alpha-sulfate, chenodeoxycholic acid 7-alpha-sulfate and unsulfated chenodeoxycholic acid were quantified in isolated perfused rat liver. Influx of the 7-alpha- and 3-alpha-sulfated derivatives was 57% and 20% that of chenodeoxycholic acid, respectively. These three compounds bound to albumin equally well, indicating that this was not a factor in their differential uptake. Although single-pass extraction of material taken up by the liver was identical. There was no difference in bile flow or biliary excretion of material taken up by the liver was identical. There was no difference in bile flow or biliary excretion rate, regardless of which bile acid sulfate was tested. These results indicate that the low plasma elimination of sulfated bile acids previously observed by others can be explained by low hepatic influx. The diminished transport into liver resulting from sulfation could lead to enhanced elimination of bile acids by the kidney.
Animals↗
S-adenosil-L-methionine is able to reverse the immunosuppressive effects of chenodeoxycholic acid in vitro.
The study was conceived to evaluate if S-adenosil-L-methionine, a substance commonly used in the treatment of cholestasis in patients with cirrhosis and chronic hepatitis, exerts any immunological effect and of it is able to counterbalance bile acid-mediated immunosuppression. Proliferation and interleukin 2 and interferon-gamma secretion of human lymphocytes, collected from healthy subjects and exposed to mitogenic stimuli (phytohemagglutinin, pokeweed and anti-CD3 monoclonal antibodies), were analysed in the basal condition or after exposure to S-adenosil-L-methionine and/or chenodeoxycholic acid. Chenodeoxycholic acid inhibited phytohemagglutinin-induced lymphocyte proliferation and interferon-gamma secretion, and phytohemagglutinin and pokeweed-mediated interleukin 2 secretion. S-adenosil-L-methionine did not affect lymphocyte proliferation while it reduced interleukin 2 secretion upon phytohemagglutinin and pokeweed stimulation and interferon-gamma secretion upon all stimuli tested. Moreover, S-adenosil-L-methionine counteracted chenodeoxycholic acid-mediated inhibition of lymphocyte proliferation and interleukin 2 secretion. The results of our study confirm the immunosuppressive role of chenodeoxycholic acid on both secretive and proliferative lymphocyte functions and provide evidence of immunomodulatory activities of S-adenosil-L-methionine and its capacity to antagonize chenodeoxycholic acid-mediated inhibition of lymphocyte proliferation and interleukin 2 secretion.
Antibodies, Monoclonal↗
Prevention of toxicity to isolated hepatocytes by liposome entrapment of chenodeoxycholic acid.
Cellular uptake and cytotoxicity of chenodeoxycholic acid, delivered free or encapsulated in liposomes, were compared in isolated rat hepatocytes. As quantified by leakage of cytoplasmic and lysosomal enzymes into the medium, cells exposed to free chenodeoxycholic acid displayed a dose-dependent cytotoxic response. Cellular uptake of the drug was either similar or less for free than for entrapped chenodeoxycholic acid at 100 to 400 microM. However, the cytolytic changes were prevented when the cells were exposed to liposome-encapsulated drug. The prevention of cytotoxicity by delivering the drug entrapped in liposomes indicates that the free drug has the capacity to injure cell membranes directly, and suggests that drug-membrane interactions play a role in the hepatotoxic potential of chenodeoxycholic acid.
Animals↗
Effect of chenodeoxycholic acid feeding during gestation in the rat on bile acid metabolism and liver morphology.
Chenodeoxycholic acid (CDCA) was fed to pregnant rats at the 0.25% level in the diet from Day 11 of gestation to delivery in order to evaluate the effects on (1) maternal tissue bile acid composition, (2) neonatal tissue bile acid composition and cholesterol-7 alpha-hydroxylase activity, and (3) maternal, neonatal, and postnatal liver morphology. Feeding CDCA increased maternal lithocholic acid while significantly decreasing deoxycholic acid, cholic acid, and total bile acids. Feeding CDCA resulted in a significantly higher chenodeoxycholic acid pool in the neonates while neonatal plasma cholesterol and the 7 alpha-hydroxylation of cholesterol was not significantly affected. Morphological examination of maternal, neonatal, and postnatal rat liver revealed no significant hepatotoxicity. This investigation has shown that (a) neonates of CDCA fed dams have a significantly greater pool of CDCA, suggesting maternal-to-fetal transfer of dihydroxy bile acids, (b) neonatal cholesterol-7 alpha-hydroxylase activity and total tissue bile acid pools are not significantly altered by increased pool of CDCA, and (c) no hepatotoxic effects on maternal, neonatal, and postnatal livers were evident with gestational feeding of CDCA at the 0.25% level in the rat.
Animals↗
Comparison of a monitored dose with a standard dose of chenodeoxycholic acid for gallstone dissolution.
The ability of chenodeoxycholic acid to dissolve gallstones was compared using different dosage regimens in two groups of 21 patients. The groups were closely matched for patient factors and stone characteristics known to influence the outcome of dissolution treatment. The patients in one group received a standard dose of chenodeoxycholic acid (15 mg/kg/day) taken at mealtimes. The patients in the second group received a bedtime dose of chenodeoxycholic acid which was sufficient to result in a proportion of this bile acid of 70% in the bile acid pool. This dose was monitored using serum bile acid profiles and varied within this test group (range 5.1-13.9 mg/kg/day). The number of patients whose stones completely dissolved in 12 months was similar in the standard-dose (7 of 21) and monitored-dose (8 of 21) groups. These results suggest that a bedtime dose of chenodeoxycholic acid, which is monitored to produce a level of 70% chenodeoxycholic acid in the biliary bile acid pool, is lower than the standard dose taken after meals but is of comparable efficacy. Lower dosage has the advantage of reducing costs and side effects from the drug, although serum bile acid profiling increases the cost of treatment.
Adult↗
[Effect of ursodeoxycholic acid on bile secretion and bile components. Comparison with chenodeoxycholic acid and dehydrocholic acid].
Effects of some bile acids on the biliary flow, BSP output and composition (phospholipid, cholesterol, bilirubin and bile acids) were studied in dogs. Ursodeoxycholic acid (UD), chenodeoxycholic acid (CD) and dehydrocholic acid (DC) caused a dramatic increase in biliary flow and BSP output. Relative potencies of these effects were DC greater than CD greater than or equal to UD. UD increased the phospholipid, bile acids and cholesterol concentration but had little effect on bilirubin concentration. Furthermore, UD greatly increased the output of four bile components. CD slightly decreased the phospholipid, cholesterol and bilirubin concentration without the bile acids, while CD increased the output of bile components. After UD or CD administration, the bile acid of each appeared markedly in the bile, dose dependently. On the other hand, DC caused a dramatic decrease of phospholipid, cholesterol and bilirubin concentration but had little effect on bile acids concentration. Output of bile components was increased by DC the first 1 hr but decreased at 2 hr. After DC administration, 3alpha, 7alpha-dihydroxy-12keto-5beta-cholanic acid appeared in the bile while DC did not. Therefore, it is concluded that UD and CD are cholanereticas and DC is a hydrocholeretica.
Animals↗
Direct measurement of hepatic extraction of chenodeoxycholic acid and ursodeoxycholic acid in man.
1. The hepatic extraction ratios of chenodeoxycholic acid and ursodeoxycholic acid have been measured in 12 patients without, and 20 patients with, liver disease. 2. Ten of the patients without liver disease were studied during cardiac catheterization, with a continuous infusion technique. Two of the patients without liver disease and all those with liver disease received an intravenous bolus of [14C]chenodeoxycholic acid or [14C]ursodeoxycholic acid, during transvenous liver biopsy. 3. The extraction ratio of chenodeoxycholic acid was 0.63 +/- 0.03 (mean +/- mean +/- SEM) and of ursodeoxycholic acid 0.53 +/- 0.01, in the patients without liver disease. In those with mild liver disease, extraction was slightly impaired (chenodeoxycholic acid; 0.49 +/0 0.03; ursodeoxycholic acid: 0.43 +/- 0.05), whereas in those with more severe liver disease it was greatly reduced (chenodeoxycholic acid: 0.16 +/- 0.08; ursodeoxycholic acid: 0.07 +/- 0.01). 4. The results suggest that (a) direct measurements confirm the accuracy of indirect estimates of hepatic extraction of chenodeoxycholic acid, (b) hepatic extraction of chenodeoxycholic acid is lower than that of cholic acid and glycocholic acid, but higher than that of ursodeoxycholic acid, (c) progressive impairment of the extraction ratios of these two bile acids occurs as the severity of liver disease increases, and (d) the ratios are correlated with indocyanine green extraction ratios.
Adult↗
Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis.
Bile acid synthesis, determined by conversion of [4-14C]cholesterol into bile acids in rat and human hepatocytes and by measurement of mass production of bile acids in rat hepatocytes, was dose-dependently decreased by cyclosporin A, with 52% (rat) and 45% (human) inhibition of 10 microM. The decreased bile acid production in rat hepatocytes was due only to a fall in the synthesis of beta-muricholic and chenodeoxycholic acids (-64% at 10 microM-cyclosporin A), with no change in the formation of cholic acid. In isolated rat liver mitochondria, 26-hydroxylation of cholesterol was potently inhibited by the drug (concn. giving half-maximal inhibition = 4 microM). These results suggest that cyclosporin A blocks the alternative pathway in bile acid synthesis, which leads preferentially to the formation of chenodeoxycholic acid.
Animals↗
Influence of cholic and chenodeoxycholic acid on biliary cholesterol secretion in man.
The interrelationships between biliary bile acid, lecithin and cholesterol secretion rates were studied druing depletion of the bile acid pool and during duodenal administration of cholic or chenodeoxycholic acid in thirteen patients 7-12 days after operation for uncomplicated gallstone disease. The mean lecithin secretion rate was signigicantly higher during cholic acid than during chenodeoxycholic acid infusion. The relationship between bile acid and cholesterol secretion rates was curvilinear, y = x/(a + bx) during bile acid pool depletion and during duodenal cholic acid infusion. At low bile acid secretion rates, during bile acid pool depletion and during cholic acid infusion, the lecithin secretion rate was significantly correlated to the cholesterol secreation rate. The bile acid and cholesterol secretion rates were not significantly correlated during chenodeoxycholic acid infusion. However, under this experimental condition a significant curvilinear relationship between lecithin and cholesterol secretion rates was found. The hepatic bile became unsaturated in cholesterol at significantly lower bile acid secretion rate during chenodeoxycholic acid infusion (10.7 +/- 0.3 mumol min-1) than during cholic acid infusion (15.6 +/- 0.5 mumol min-1).
Aged↗
Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid.
We studied the effect of chenodeoxycholic acid in 17 patients with cerebrotendinous xanthomatosis. Before treatment, all subjects were symptomatic, with Achilles tendon xanthomas (in 15 of 17), cataracts (in 12 of 17), dementia (in 13 of 17), pyramidal-tract signs (in all 17), cerebellar dysfunction (in 13 of 17), mild peripheral neuropathy (in 7 of 17), electroencephalographic abnormalities (in 10 of 13), and abnormal cerebral computerized axial tomographic scans (in 10 of 12). After at least one year of chenodeoxycholic acid treatment (750 mg per day), dementia cleared in 10 subjects, and pyramidal and cerebellar signs disappeared in 5 and improved in another 8. Peripheral neuropathy was no longer detected in six. The electroencephalogram became normal in five and showed fewer abnormalities in another three subjects. Cerebral computerized axial tomographic scans improved in seven patients; the changes included the disappearance of a cerebellar xanthoma in one case. Concomitantly, mean plasma cholestanol levels declined threefold, and abnormal bile acid synthesis was suppressed. We conclude that long-term therapy with chenodeoxycholic acid may correct the biochemical abnormalities and arrest and possibly reverse the progression of cerebrotendinous xanthomatosis.
Adolescent↗
An in vivo evaluation of the quantitative significance of several potential pathways to cholic and chenodeoxycholic acids from cholesterol in man.
The present study was designed to obtain more definitive information in man on the metabolic pathways to chenodeoxycholic acid and to cholic acid via a pathway not involving an initial 7 alpha-hydroxylation of cholesterol. Four bile fistula patients were administered consecutively two or more of the following 3H-labeled bile acid intermediates: 7 alpha-hydroxycholesterol, 7 alpha-hydroxy-4-cholesten-3-one, 5 beta-cholestane 3 alpha,7 alpha,26-triol, 26-hydroxycholesterol,7 alpha,26-dihydroxy-4-cholesten-3-one, and 5-cholestene-3 beta,12 alpha-diol. Both 7 alpha-hydroxy[7 beta-3H]cholesterol and 7 alpha-hydroxy-4-[6 beta-3H]cholesten-3-one were efficiently converted to bile acids and preferred chenodeoxycholic acid over cholic acid. The specific activity time curves indicated that a portion of cholic acid synthesis did not pass through 7 alpha-hydroxycholesterol. [3H]26-Hydroxycholesterol and [3H]-5-cholestene 3 beta,12 alpha-diol, two potential intermediates of this bypass pathway to cholic acid, were poorly converted to primary bile acids (10 to 27%). The [3H]26-hydroxycholesterol preferred chenodeoxycholic over cholic acid by about 4 to 1. The [3H]5-cholestene 3 beta,12 alpha-diol formed cholic acid in low yield (10 to 20%). It is concluded that pathways to primary acids from cholesterol through 26-hydroxycholesterol and 5-cholestene 3 beta,12 alpha-diol are probably of minor quantitative significance. A selective pathway to chenodeoxycholic acid via 26-hydroxylation of 7 alpha-hydroxy-4-cholesten-3-one was also investigated. The 5 beta-cholestane 3 alpha,7 alpha,26-triol was converted in about equal amounts to cholic and chenodeoxycholic acids. The 7 alpha-hydroxy-4-cholesten-3-one was also efficiently converted to both bile acids but preferred chemodeoxycholic acid. The most efficient precursor of chenodeoxycholic acid was 7 alpha,26-dihydroxy-4-cholesten-3-one, which was efficiently converted to primary bile acids; chenodeoxycholic acid was preferred over cholic acid by approximately 7 to 1. These findings suggest the presence of a major pathway to chenodeoxycholic acid via the 26-hydroxylation of 7 alpha-hydroxy-4-cholesten-3-one and intermediate formation of 7 alpha,26-dihydroxy-4-cholesten-3-one.
Bile↗
Differing effects of ursodeoxycholic or chenodeoxycholic acid on biliary cholesterol saturation and bile acid metabolism in man. A dose-response study.
A dose-response study comparing ursodeoxycholic and chenodeoxycholic acid was carried out in six men with asymptomatic radiolucent gallstones present in well-visualizing gallbladders. The study tested the effects of a low (averaging 6 mg/kg/day) or medium dose (averaging 11 mg/kg/day) of each bile acid on the cholesterol saturation of bile as well as on bile acid metabolism, as inferred from biliary and fecal bile acid composition. Ursodeoxycholic acid, at low or medium doses, induced bile desaturation in most patients, whereas chenodeoxycholic acid did not. Despite the greater desaturation efficacy of ursodeoxycholic acid, biliary bile acids became less enriched with the administered bile acid during ursodeoxycholic acid treatment than during chenodeoxycholic acid treatment. Both bile acids were nearly completely 7-dehydroxylated to lithocholic acid by colonic bacteria, but biliary lithocholic increased only slightly (and similarly) with each bile acid. Fecal bile acid composition suggested that administered ursodeoxycholic acid suppressed endogenous bile acid synthesis much less than chenodeoxycholic acid. The results indicate that ursodeoxycholic acid and chenodeoxycholic acid have similar but not identical effects on bile acid metabolism, but that for a given dose, ursodeoxycholic acid is a more potent desaturating agent than chenodeoxycholic acid. The results suggest that cholesterol gallstone dissolution with ursodeoxycholic acid should occur with a dose of 8-10 mg/kg in most nonobese patients.
Aged↗