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PubMed1987

Increased concentrations of cholestanol and apolipoprotein B in the cerebrospinal fluid of patients with cerebrotendinous xanthomatosis. Effect of chenodeoxycholic acid.

We investigated the effect of chenodeoxycholic acid on cerebrospinal fluid sterol and protein composition in six patients with cerebrotendinous xanthomatosis, a progressive neurologic disease, and in 11 control subjects. In the cerebrospinal fluid from the controls, the mean (+/- SD) levels of cholesterol and cholestanol were 400 +/- 300 and 4 +/- 7 micrograms per deciliter, respectively. The levels were almost 1.5 and 20 times higher in cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis. Cholestanol levels were also markedly elevated in the plasma of untreated patients, but their plasma cholesterol levels (215 +/- 61 mg per deciliter) were not different from control values. Treatment with chenodeoxycholic acid reduced cerebrospinal fluid cholesterol by 34 percent and cholestanol threefold. Plasma cholestanol levels also decreased sharply. Normal cerebrospinal fluid contained small quantities of albumin, apolipoproteins, and lecithin:cholesterol acyltransferase. In cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis, immunoreactive apolipoprotein B or apolipoprotein B fragment was increased about 100-fold and albumin about 3.5-fold; apolipoprotein AI, apolipoprotein D, and lecithin:cholesterol acyltransferase were 1.5 to 3 times more concentrated. Apolipoprotein AIV and apolipoprotein E concentrations were comparable to those in controls, and apolipoprotein AII was considerably decreased. During treatment, the concentrations of albumin and apolipoproteins AI and B declined. These results suggest that increased cerebrospinal fluid sterols are derived from plasma lipoproteins by means of a defective blood-brain barrier in patients with cerebrotendinous xanthomatosis. Therapy with chenodeoxycholic acid reestablished selective permeability of the blood-brain barrier and normalized the concentrations of sterol and apolipoprotein in the cerebrospinal fluid.

Albumins↗
PubMed1983

The metabolism of chenodeoxycholic acid to beta-muricholic acid in rat liver.

1. The synthesis of conjugated chenodeoxycholic acid and tauro-beta-muricholic acid in isolated rat hepatocytes was measured by radioimmunoassay. Production of tauro-beta-muricholic acid was linear over 4 h of incubation at 37 degrees C. The net synthesis of conjugated chenodeoxycholic acid was very much lower than that of tauro-beta-muricholic acid. 2. When hepatocytes were prepared from rats in which the enterohepatic circulation had been broken, either by feeding the bile salt sequestrant, cholestyramine or by total biliary drainage for 48 h, synthesis of tauro-beta-muricholic acid was increased compared to that in cells from control rats. Conjugated chenodeoxycholic acid accumulation during incubation of the hepatocytes was increased by cholestyramine feeding but not by total biliary drainage. These results suggest that there is a metabolic difference between the two methods of breaking the enterohepatic circulation with regard to chenodeoxycholic acid synthesis. 3. Hepatocytes prepared from rats given 1% cholesterol in the diet for at least 2 weeks synthesised significantly more tauro-beta-muricholic acid than those from control rats. The total amount of conjugated cholic, chenodeoxycholic and tauro-beta-muricholic acids synthesised by cells from cholesterol fed animals, however was not significantly different from that produced by hepatocytes from normal rats. 4. Exogenous taurochenodeoxycholic acid was metabolised to tauromuricholic acid by isolated hepatocytes. Production of tauro-beta-muricholic acid reached a maximum at a concentration of 20 microM taurochenodeoxycholic acid. The total metabolism of taurochenodeoxycholic acid, however, increased linearly up to the highest concentration measured, 50 microM. 5. The biliary content of tauro-beta-muricholic acid during total biliary drainage fell rapidly in the first 10 h and thereafter continued to decline, reaching a minimum after about 24 h. No significant rise was observed during the remainder of the experimental period. 6. It is concluded that a large proportion of the conjugated chenodeoxycholic acid synthesised by isolated hepatocytes in vitro is metabolised to tauro-beta-muricholic acid, and therefore it is necessary to take this into account when using this system to study bile salt synthesis.

Animals↗
PubMed1976

Hepatic toxicity in the rhesus monkey treated with chenodeoxycholic acid for 6 months: biochemical and ultrastructural studies.

The long term administration of chenodeoxycholic acid in man has to be regarded with caution because chenodeoxycholic acid has caused liver damage in various species of animals, including primates. To study the effect of three doses of chenodeoxycholic acid (10, 40, and 100 mg per kg per day) on hepatic function and morphology, biliary bile acid composition and the reversibility of changes were investigated in 22 rhesus monkeys. After 6 months of treatment with 40 and 100 mg per kg per day, bile duct proliferation, portal tract inflammation and fibrosis, bile canalicular bleb formation, and hypertrophy of the smooth endoplasmic reticulum were associated with elevated serum levels of oxaloacetic transaminase, glutamic pyruvic transaminase, and leucine aminopeptidase. In the bile, the proportion of chenodeoxycholic acid and its bacterial metabolite, lithocholic acid, rose to approximately 85 and 10% of the total bile acids. After chenodeoxycholic acid was withdrawn for 3 months, the hepatic morphological lesions persisted in some animals although biliary bile acid composition returned to normal. No hepatic abnormalities were seen in the animals treated with 10 mg per kg per day. The findings suggest that long term treatment of rhesus monkeys with high doses of chenodeoxycholic acid results in severe hepatic histological lesions that can persist after discontinuation of the bile acid.

Alanine Transaminase↗
PubMed1977

Suitability of [11, 12-3H2]chenodeoxycholic acid and [11, 12-3H2]lithocholic acid for isotope dilution studies of bile acid metabolism in man.

Studies were carried out to assess the stability of the label in [11,12-(3)H(2)]chenodeoxycholic acid and [11,12-(3)H(2)]lithocholic acid during enterohepatic cycling and thus define the suitability of these tracers for isotope dilution studies of bile acids in man. To do this, [11,12-(3)H(2)]-chenodeoxycholic acid and [24-(14)C]chenodeoxycholic acid were administered simultaneously to six healthy adults. The (3)H/(14)C ratio of biliary chenodeoxycholic acid and the specific activity of biliary chenodeoxycholic acid were determined to permit calculation of pool size and turnover rate by the conventional isotope dilution procedure of Lindstedt (1957. Acta Physiol. Scand. 40: 1). Excretion of label in urine was measured as well as the (3)H/(14)C ratio of fecal bile acids. Similar studies were carried out with [11,12-(3)H(2)]lithocholic acid and [24-(14)C]lithocholic acid. With [11,12-(3)H(2)]chenodeoxycholic acid, 10-15% of the label was lost during the first 24 hours, after which the (3)H/(14)C ratio of biliary chenodeoxycholic acid remained constant. The loss of (3)H caused a consistent overestimate of pool size by 10-15%, but since the fractional turnover rate of the two isotopes was identical, the calculated rate of synthesis was 10-15% greater when determined using (3)H. The loss of (3)H was attributed to the presence of (3)H in positions other than 11 and 12 occurring during the labeling procedure when the unsaturated precursor was exposed to carrier-free tritium gas. The (3)H/(14)C ratio of feces was consistently below that of bile, suggesting bacterial removal of additional (3)H during distal intestinal passage. In contrast, [11,12-(3)H(2)]lithocholic acid lost (3)H continuously, so that by 2 days after administration, the (3)H/(14)C ratio had fallen to nearly half of that of the administered mixture. It is concluded that isotope dilution studies may be carried out with one preparation of [11,12-(3)H(2)]chenodeoxycholic acid with an error of 10-15%; possibly a more stable preparation can be prepared with a gentler tritiation procedure. One preparation of [11,12-(3)H(2)]lithocholic acid was unsatisfactory for isotope dilution studies in man.

Adult↗
PubMed1975

Biliary lipid output during three meals and an overnight fast. II. Effect of chenodeoxycholic acid treatment in gallstone subjects.

Oral treatment with chenodeoxycholic acid causes dissolution of cholesterol gallstones in man. In order to determine the mechanism of this effect, we have measured 24-hour biliary lipid output, lipid composition of fasting gallbladder bile, and bile acid pool sizes before and during such treatment in six patients with radiolucent gallstones in functioning gallbladders. In all six patients, the degree of cholesterol saturation of fasting-state gallbladder bile was decreased during treatment to a level below the thermodynamic solubility line. This effect was due to a decrease in biliary cholesterol output, associated with conversion of more than 90% of the total bile acid pool to chenodeoxycholic acid. It could not be attributed to an increase in total bile acid pool size nor to an increase in biliary bile acid or phospholipid output.

Administration, Oral↗
PubMed2006

Human UDP-glucuronosyltransferase (UGT)1A3 enzyme conjugates chenodeoxycholic acid in the liver.

Chenodeoxycholic acid (CDCA) is a liver-formed detergent and plays an important role in the control of cholesterol homeostasis. During cholestasis, toxic bile acids (BA) accumulate in hepatocytes causing damage and consequent impairment of their function. Glucuronidation, a conjugation reaction catalyzed by UDP-glucuronosyltransferase (UGT) enzymes, is considered an important metabolic pathway for hepatic BA. This study identifies the human UGT1A3 enzyme as the major enzyme responsible for the hepatic formation of the acyl CDCA-24glucuronide (CDCA-24G). Kinetic analyses revealed that human liver and UGT1A3 catalyze the formation of CDCA-24G with similar K(m) values of 10.6 to 18.6 mumol/L, respectively. In addition, electrophoretic mobility shift assays and transient transfection experiments revealed that glucuronidation reduces the ability of CDCA to act as an activator of the nuclear farnesoid X-receptor (FXR). Finally, we observed that treatment of human hepatocytes with fibrates increases the expression and activity of UGT1A3, whereas CDCA has no effect. In conclusion, UGT1A3 is the main UGT enzyme for the hepatic formation of CDCA-24G and glucuronidation inhibits the ability of CDCA to act as an FXR activator. In vitro data also suggest that fibrates may favor the formation of bile acid glucuronides in cholestatic patients.

Adult↗
PubMed1980

Intestinal solubilization, absorption, pharmacokinetics and bioavailability of chenodeoxycholic acid.

Little is known about the physical state, intestinal solubilization, absorption and bioavailability of chenodeoxycholic acid used in the medical treatment of gallstones. Therefore the concentrations of unconjugated chenodeoxycholic acid were measured in the supernatant and precipitate phases of intestinal contents aspirated from stomach, duodenum and jejunum of nine control subjects who took 500 mg chenodeoxycholic acid (4 X 125 mg gelatin-coated capsules) either fasting or together with a standard liquid meal. Chenodeoxycholic acid solubility was markedly influenced by luminal pH but was little affected by endogenous conjugated bile acids when their concentrations were > 1-2 mmol/l. Systemic bioavailability of 250, 500 and 750 doses of chenodeoxycholic acid was measured in five subjects by comparing areas under 4 h serum concentration-time curves after giving the bile acid first as a bolus intraduodenal aqueous infusion of 3H-labelled chenodeoxycholic acid containing either 14C-polyethylene glycol or bromsulphthalein as non-absorbable markers, and then as gelatin-coated capsules by mouth. Absorption was assessed by measuring the ratio of marker: bile acid in intestinal contents aspirated for 2 h from sites 60 and 120 cm distal to the duodenal infusion port and in three subjects quantitative recovery of marker was measured proximal to an occluding intestinal balloon. Absorption of duodenally-infused chenodeoxycholic acid was 96-99% complete and bioavailability was complete with the 250 and 500 mg doses but fell to 81% with the 750 mg dose.

Adult↗
PubMed1975

[In vivo dissolving of gall-stones: the effect of chenodeoxycholic acid. (author's transl)].

Chenodeoxycholic acid (CDCA) was administered for an average of 15 months to 14 patients with gall-stones. The gall-stones were radiolucent in all but one instance (solitary calcified stone). Stones dissolved completely after 12 and 15 months of therapy, respectively, in two patients, while in four the size of the stones diminished. No change occurred in the remaining patients. In five patients multiple stones dissolved, while in one a radiolucent solitary stone dissolved. In one patient, with a negative cholecystogram for a time before being treated with CDCA, the gall-bladder perforated while on treatment. CDCA was well tolerated by all patients: upper abdominal discomfort disappeared during CDCA treatment in two patients and improved in nine. Only side-effect was occasional mild diarrhoea in five patients. Bile was analysed in seven patients, supersaturation with cholesterol being found in five. Biliary lipid composition became normal during CDCA treatment in these five patients. Serum triglyceride levels fell during CDCA administration in ten of eleven patients in which serum measurements were made; the greatest fall occurred in the five patients with hypertriglyceridaemia. The fall in triglyceride levels was associated with a diminution of the pre-beta-lipo-protein fraction and the chylomicron fraction. No significant change occurred in serum cholesterol levels.

Adult↗
PubMed1981

Serum bile acids after test meals and oral load of chenodeoxycholic acid.

The serum levels of conjugated cholic (CA) and chenodeoxycholic acid (CDA) were studied in 15 healthy individuals before and during 3 h after two different test meals and an oral load of CDA. The solid test meal containing 35 g fat gave less and earlier increases of CA and CDA than the liquid test meal containing 50 g fat. These findings demonstrate that the postprandial pattern of serum bile acids depends on the test meal used. After oral intake of 1 g CDA, serum levels of CDA rose faster than after the test meals, and mean maximal levels were reached after 90 min. The oral CDA loading test was also performed in 11 patients with chronic hepatitis. The results indicate that in patients with normal fasting CDA levels, this test may detect liver dysfunction. The advantages of an oral bile acid load over test meals are pointed out.

Administration, Oral↗
PubMed1987

Diagnostic value of serum immunoreactive conjugated cholic or chenodeoxycholic acids in detecting hepatobiliary diseases. Comparison with levels of 3 alpha-hydroxy bile acids determined enzymatically and with routine liver tests.

The diagnostic value of the enzymatic fluorometric method for total serum bile acids (TSBA) and for radioimmunoassay measurement for conjugated cholic acid (CCA) or chenodeoxycholic acid was compared with that of routine liver function tests in 223 patients with liver disease, 88 healthy subjects, and 118 patients affected by other diseases. The value of the tests for screening in the general population was assessed by simulation, using estimates of disease prevalence. TSBA was significantly more sensitive (78%) but less specific (94%) than CCA (sensitivity of 69%, specificity of 98%). Aspartate aminotransferase was nearly as sensitive (74%) as TSBA, but significantly less specific (93%) than CCA. CCA provided the highest positive predictivity (98%), even in a screening simulation (32%). With the use of sequential aspartate aminotransferase measurement followed by CCA, this value rose to 100%. This test procedure appears to be the best screening method for liver diseases available at present.

Adolescent↗
PubMed1982

Conjugation and excretion of 14C-chenodeoxycholic acid during total extrahepatic cholestasis.

14C-chenodeoxycholic acid was administered intravenously to two patients with total extrahepatic cholestasis subjected to external biliary drainage 38 and 132 h after administration. The disappearance from serum and the renal and hepatic excretion of labelled compounds were followed. Labelled conjugates were separated chromatographically and quantified. Two hours after administration almost all radioactivity in the serum was in the form of glycine or taurine conjugates and after 36 h about 20% of the labelled conjugates in serum were sulphates. The disappearance of radioactivity from the serum was slow, due to low renal elimination. Almost all the chenodeoxycholic acid excreted in the urine was sulphated. During the biliary drainage only a minor portion of the labelled chenodeoxycholic acid administered was excreted in the bile; hepatic elimination did not exceed the concomitant renal excretion.

Aged↗
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↗
PubMed1976

Influence of cholic and chenodeoxycholic acid on canalicular bile flow in man.

Hepatic bile flow was measured and hepatic [(14C]mannitol clearance was calculated during depletion of the bile acid pool and during duodenal administration of cholic or chenodeoxycholic acid in 10 patients 7 to 12 days after operation for uncomplicated gallstone disease. The relationship between [(14)C]mannitol clearance and bile flow was linear, with a regression coefficient which was not significantly different from unity. This finding supported the assumption that mannitol clearance can be used as a measure of canalicular bile flow in man. Linear relationships between bile acid secretion rate and bile flow and bile acid secretion rate and [(14)C]mannitol clearance were found during depletion of the bile acid pool (secretion of cholic, chenodeoxycholic, and deoxycholic acids; relative concentrations, 1.0:1.0:0.5) as well as during cholic acid infusion (73 +/- 3% cholic acid in the secreted hepatic bile) and during chenodeoxycholic acid infusion (88 +/- 2% chenodeoxycholic acid in the secreted hepatic bile). The bile flow dependence on bile acids 0.011 +/- 0.002 ml mumoles(-1)) was not significantly different for "mixed" bile acid secretion, mainly cholic acid secretion, or mainly chenodeoxycholic acid secretion. Neither was the ductular bile flow (0.08 +/- 0.03 ml min(-1)) significantly influenced by the various experimental conditions. The canalicular flow--the bile acid-independent (0.17 +/- 0.05 ml min(-1)) and the bile acid-dependent flow--constituted 70 to 85% of the total bile flow. It is concluded that secretion of cholic acid and of chenodeoxycholic acid promote the same bile flow volume per micromole in man.

Aged↗
PubMed1975

[Conjugation of chenodeoxycholic acid and cholic acid during passage through liver].

Both chenodeoxycholic acid, in the dosage administered for dissolution of gallstones, and cholic acid are completely conjugated during one passage through the liver. The glycine:taurine ratio increases with the cumulative amount of exogenous bile acids secreted, which suggests consumption of available taurine. Since conjugation with glycine compensates for deficiency of the taurine conjugating system, it can be assumed that in the normal liver and with doses not exceeding 2.5 mmoles, chenodeoxycholic acid is efficiently and completely transformed into its "physiologic" conjugated form.

Bile Acids and Salts↗
PubMed1982

Interaction of chenodeoxycholic acid and dietary cholesterol in the treatment of cholesterol gallstones.

Standard doses of chenodeoxycholic acid (15 mg/kg/day) fail to dissolve gallstones in 30 to 50 percent of patients with radiolucent gallstones in a functioning gallbladder. In humans, increasing dietary cholesterol produces increased biliary secretion of cholesterol. Restriction of dietary cholesterol reduces the minimum effective dose of chenodeoxycholic acid and speeds gallstone dissolution. In this study we investigated the interaction of dietary cholesterol and chenodeoxycholic acid in the prevention of gallstones in the prairie dog gallstone model. In animals fed a moderately lithogenic diet, standard doses of chenodeoxycholic acid failed to prevent gallstones. Reduction of the cholesterol stimulus or doubling the dose of chenodeoxycholic acid prevented the formation of gallstones. These findings support the hypothesis that the formation and dissolution of cholesterol gallstones are an expression of the relative strengths of saturating and desaturating stimuli. Therefore, rational therapy for cholesterol gallstone dissolution and prevention requires both reduction of lithogenic stimuli and optimal titration of chenodeoxycholic acid.

Animals↗
PubMed1982

Isolation and characterization of rat liver microsomal UDP-glucuronosyltransferase activity toward chenodeoxycholic acid and testosterone as a single form of enzyme.

Microsomal UDP-glucuronosyltransferase activity toward chenodeoxycholic acid and testosterone has been isolated from rat liver and appears to be homogeneous in sodium dodecyl sulfate gel electrophoresis and polyacrylamide gradient gel electrophoresis. The conjugating activities toward chenodeoxycholic acid and testosterone co-purified and showed identical mobilities in disc gel electrophoresis, indicating that chenodeoxycholic acid and testosterone are glucuronidated by a single form of enzyme. UDP-glucuronosyltransferase activities toward estrone, bilirubin, 4-nitrophenol, and morphine did not co-purify with the activity toward chenodeoxycholic acid and testosterone and were not detectable in the pure enzyme in the presence or absence of phospholipids. In addition to glucuronic acid conjugation, the enzyme is able to catalyze galacturonic acid conjugation of chenodeoxycholic acid and testosterone. The enzyme has a subunit Mr approximately 54,000 and in the presence of the stabilizing detergent chenodeoxycholic acid, it appears to exist as an aggregate with an apparent Mr = 318,000 as estimated by gel filtration and 316,000 by polyacrylamide gradient gel electrophoresis.

Animals↗
PubMed1986

Chenodeoxycholic acid therapy in erythrohepatic protoporphyria.

The short-term effect of chenodeoxycholic acid administration on the excretion of protoporphyrin was investigated in 5 patients suffering from erythrohepatic protoporphyria. Faeces were collected for 7 days, 10 ml of bile was sampled daily and blood was drawn every 2 to 3 days. Chenodeoxycholic acid was given in a dosage of 15 mg/kg/day from the 8th day. Collection of faeces, bile and blood was then continued for 10 more days. Protoporphyrin concentration was measured by high-pressure liquid chromatography and fluorometry. Following the administration of chenodeoxycholic acid the concentration of protoporphyrin in faeces and bile decreased significantly. In addition, all patients showed a significant decrease in erythrocyte protoporphyrin concentration. These results indicate that chenodeoxycholic acid therapy causes a marked decrease in the excretion of protoporphyrin in patients with erythrohepatic protoporphyria. The subsequent decrease in erythrocyte protoporphyrin suggests that chenodeoxycholic acid inhibits the production of protoporphyrin in the liver.

Chenodeoxycholic Acid↗