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Results for “CHOLIC ACID”

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PubMed1993

Metabolism of 5 beta-cholestane-3 alpha,7 alpha-diol in ileectomized rats.

The effect of ileectomy on the composition of biliary bile acids and the metabolism of 5 beta-cholestane-3 alpha,7 alpha-diol was studied in rats. In the ileectomized rats, there was an increase in the percentage of cholic acid group (cholic acid and deoxycholic acid) as compared with the normal rats. After rats with a bile fistula were given intravenously 5 beta-[7 beta-3H] cholestane-3 alpha,7 alpha-diol, there was a 3-fold increase in the percentage of [3H]cholic acid in the ileectomized rats compared to the normal rats. The findings have suggested that an increase in the percentage of cholic acid group in the ileectomized rats is due to the increased formation of cholic acid through an alternative pathway which involves 5 beta-cholestane-3 alpha,7 alpha-diol.

Animals↗

PubMed1996

Feedback regulation of bile acid synthesis measured by stable isotope kinetics in humans.

OBJECTIVE: To investigate the effect of a low dose of exogenous bile acids and a non-absorbable antibiotic on bile acid kinetics in healthy human subjects. METHODS: Pool size, synthesis rate and fractional turnover rate of the three main bile acids were determined simultaneously with stable isotope labelled bile acids in volunteers before and during intake of 500 mg cholic acid (n = 6), chenodeoxycholic acid (n = 6) or deoxycholic acid (n = 5) per day for 4 weeks or 1 g of paromomycin (n = 6) per day for 2 weeks. RESULTS: Administration of cholic acid nearly doubled the input and pool of deoxycholic acid; chenodeoxycholic acid synthesis was inhibited by 38% and pool size was reduced by 50%. Deoxycholic acid administration resulted in a suppression of both cholic acid and chenodeoxycholic acid synthesis by 53%; the corresponding pool sizes were reduced by 64% and 57%, respectively. The degree of suppression of chenodeoxycholic acid synthesis correlated significantly (P < 0.001) with the relative change of deoxycholic acid input and pool size. Oral chenodeoxycholic acid resulted in an inhibition of cholic acid synthesis (65%) and deoxycholic acid input (67%). The effects of the antibiotic were variable. CONCLUSION: The suppressive effect of cholic acid may be mediated by deoxycholic acid, which is nearly as effective as chenodeoxycholate.

Administration, Oral↗

PubMed2001

Chiral recognition of binaphthyl derivatives: a chiral recognition model on the basis of chromatography, spectroscopy, and molecular mechanistic calculations for the enantioseparation of 1,1'-binaphthyl derivatives on cholic acid-bonded stationary phases.

In an effort to elucidate the mechanism of chiral discrimination of cholic acid-based stationary phases, the enantiomeric recognition ability of six chiral stationary phases (CSPs), prepared from differently substituted cholic acid derivatives, was evaluated in normal phase high-performance liquid chromatography (HPLC) with a series of 1,1'-binaphthyl compounds. The influence of structural variations of analytes on retention and enantioselectivity was investigated. Particularly high values of enantioselectivity were observed for the binaphthol enantiomers on a CSP prepared from the allyl 7 alpha,12 alpha-dihydroxy-3 alpha-phenylcarbamoyloxy-5 beta-cholan-24-oate. The complexes of this chiral selector with both enantiomers of binaphthol were studied as models for the interactions responsible for the enantioseparation with the cholic acid-based stationary phases. The 1:1 stoichiometry of the complex in solution was determined by UV titration. The chiral selector dissolved in chloroform exhibited a chiral discrimination for the binaphthol in (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopies. Some aromatic proton and carbon resonances of binaphthol were clearly separated into a pair of peaks due to enantiomers in the presence of the chiral selector. Moreover, on the basis of molecular mechanics calculation, a chiral discrimination model was proposed which nicely explains the relevant chromatographic behavior of the 1,1'-binaphthyl derivatives.

Journal Article↗

PubMed2004

A small-angle neutron scattering study of cholic acid-based organogel systems.

Small-angle neutron scattering measurements were performed on some cholic acid-based gel systems in order to gain detailed information about the network structure. The presence of thin fibers with a radius of about 10-20 A was found for various gelators. Two types of interaction between different sorts of fibers were demonstrated, depending on the molecular structure of the gelator. The first type involves the presence of microcrystalline knots with a dimension of about 100-200 A between the fibers. Upon heating, this network gradually disintegrates. The second type involves loose entanglements between flattened fibers. The occurrence of these types of interaction is related to the length of the alkyl tail attached to cholic acid.

Cholic Acids↗

PubMed1979

Bile acid clearance in sheep with hereditary hyperbilirubinemia.

The disappearance of IV injected [24-14C]cholic acid from plasma was studied in normal and mutant Corriedale and Southdown sheep exhibiting hereditary defects in hepatic organic anion transport. Hepatic cholic acid clearance was determined from the integral of the 40-minute disappearance curves fit to the sums of two exponential functions. Cholic acid clearance among Corriedale sheep was significantly less (P less than 0.05) for mutant sheep (8.44 +/- 0.86 SEM ml/minute/kg of body weight) than for normal sheep (12.7 +/- 0.58 ml/minute/kg). Cholic acid clearance in the Southdown mutant (1.97 +/- 0.59 ml/minute/kg) was less than 15% of normal clearance rate (13.3 +/- 2.2 ml/minute/kg). Clearance of [14C]taurocholic acid (curves fit to three exponential function) in the Southdown mutant (10.8 +/- 0.4 ml/minute/kg) was significantly greater (P less than 0.01) than cholic acid clearance, yet was not significantly different (P greater than 0.05) from normal taurocholate clearance (17.8 +/- 2.5 ml/minute/kg). Hepatic regurgitation of conjugated bile acid was not detected after [14C]cholic acid injection. Both the mutant Corriedale and Southdown sheep, which exhibited inherited defects in hepatic bilirubin transport similar to Dubin-Johnson syndrome and Gilbert's disease in man, exhibited defects in hepatic bile acid clearance.

Animals↗

PubMed1977

Effect of ethynylestradiol on biliary excretion of bile acids, phosphatidylcolines, and cholesterol in the bile fistula rat.

The effects of ethynylestradiol on endogenous bile acids, their capacity to conjugate and excrete intravenously infused cholic acid, the concentrations of biliary cholesterol and lecithin, and the individual molecular species of phosphatidylcholine have been determined in male and female Sprague-Dawley rats. Endogenous biliary bile acids were analyzed by gas-liquid chromatography-mass spectrometry. Eleven bile acids were identified and several minor bile acids, primarily muricholates, could not be completely characterized. After 5 days of treatment with ethynylestradiol (1 mg/kg per day), the percentage of cholic acid decreased and the percentage of 6beta-hydroxylated bile acids, including several monounsaturated species, increased. Ethynylestradiol caused a decrease in bile acid-independent bile flow. Intravenous infusion of cholic acid at a high concentration caused cholestasis in control animals but, after ethynylestradiol treatment, cholestasis developed during the infusion of a much lower concentration of cholate, indicating a lowered threshhold for bile acid-induced cholestasis. In the treated rats, there was a slight increase in excretion of unconjugated endogenous bile acids, and a striking impairment of conjugation of intravenously administered cholic acid. One of the few sex-related differences observed was an increased concentration of biliary phospholipids in untreated male rats. Both phospholipid and cholesterol concentrations in the bile were higher in the treated animals. The molar percentage of cholesterol was always 1-2%, but it was slightly higher in treated animals, especially males. Ethynylestradiol treatment also affected biliary phospholipid by causing a marked increase of phosphatidylcholine species containing palmitic and oleic acid residues and a decrease of species containing stearic and linoleic acid residues. There was no increase in biliary excretion of long chain polyunsaturated species, which might have indicated damage to membranes, in response to ethynylestradiol either alone or with cholic acid infusion. Some of these ethynylestradiol-induced changes in biliary bile acid and lipid excretion are probably peculiar to the rat, but others, such as the increase in molar percentage of cholesterol and cholestasis, may be relevant to disorders in man, especially cholesterol gallstones and idiopathic cholestasis of pregnancy.

Animals↗

PubMed1977

Bile acid malabsorption--a consequence of terminal ileal dysfunction in protracted diarrhea of infancy.

Fecal excretion of labeled bile acid (14C-24-cholic acid) was distinctly increased in two infants with protracted diarrhea, whereas four patients with steatorrhea due to pancreatic or mucosal abnormalities and five patients with mild chronic diarrhea had no excess fecal loss of bile acid. The loss of 14C-24-cholic acid in our patients with intractable diarrhea was similar to that observed in four infants who had undergone ileal resection. The ratio of mean 24-hour excretion of bile acid to that of a non-absorbable marker, polyethylene glycol, confirmed the malabsorption of bile acid in the patients with intractable diarrhea or ileal resection. These results differ significantly (p less than 0.05) from excretion ratios obtained in patients with either steatorrhea or chronic diarrhea. The extent of the loss of bile acid was not significantly related to the rate of fecal fat excretion. There was no direct correlation of fecal weight with the rate of bile acid excretion. Ileal function, as further assessed by the Schilling test with exogenous intrinsic factor, was grossly abnormal in both of the patients with intractable diarrhea.

Bile Acids and Salts↗

PubMed1981

Effects of rifampin on biliary lipids in humans.

Because the action of rifampin induces hepatic microsomal enzymes, a study was carried out in four patients to determine whether this drug alters the composition of biliary lipids. Several different measurements were made while patients were both on and off rifampin therapy for various infective processes. These measurements included multiple determinations of lipid composition of gallbladder bile, the relative proportions f individual bile acids, and kinetics of cholic acid and chenodeoxycholic acid. In all four patients, the saturation of gallbladder bile increased during rifampin treatment, and the bile consistently became supersaturated. The relative portions of chenodeoxycholic acid and cholic acid were essentially unchanged by treatment, but total synthesis of bile acids increased in three tested patients with rifampin therapy. These results indicate that rifampin increases saturation of bile with cholesterol, but this increase is not due to a reduction in bile acid production.

Adult↗

PubMed2006

Molecular adsorbent recirculating system (MARS) application in liver failure: clinical and hemodepurative results in 22 patients.

PURPOSE: Acute liver failure (ALF) and acute on chronic liver failure (ACLF) still show a poor prognosis. MARS was used in 22 patients with ALF or ACLF to prolong patient survival for liver function recovery or as a bridge to transplantation. DESIGN: Evaluation of depurative efficiency, biocompatibility, hemodynamics, encephalopathy (HE) and clinical outcome. PROCEDURES: During 71 five-hour sessions we evaluated (0', 60', 120', 180', 240', 300'): bilirubin, ammonia, cholic acid (CCA), chenodeoxycholic acid (CCDCA), leukocytes, platelets, hemoglobin and mean arterial pressure (MAP). Serum creatinine, electrolytes, cardiac output, cardiac index (bioimpedence) and HE (West Haven Criteria score) were evaluated at 0' and 300'. STATISTICAL METHODS AND OUTCOME MEASURES: Student's t-test for pre- vs. end-session values was used. For bilirubin and ammonia the correlation test was made between pre- and end-session values and between pre-session values and removal rates (RRS). MAIN FINDINGS: Survival was 90.9% at 7 days, 40.9% at 30 days. Pre- vs. end-session: bilirubin from 37.2 +/- 12.5 mg/dL to 24.9 +/- 8.9 mg/dL (p < 0.01), ammonia from 88.0 +/- 60.4 micromol/L to 43.6 +/- 32.9 micromol/L (p < 0.01), CCA from 42.8 +/- 21.0 micromol/L 18.2 +/- 9.8 micromol/L (p < 0.01), CCDCA from 26.3 +/- 6.3 micromol/L to 15.7+/-7.6 micromol/L (p<0.01). The correlation test between pre-session values of bilirubin and ammonia vs. RR S was respectively 0.32 (p = 0.01) and 0.30 (p = 0.04). Leukocytes, platelets and hemoglobin remained stable. MAP increased from 82.0 +/- 12.0 mmHg to 87.0 +/- 13.0 mmHg (p < 0.05), West Haven Criteria score decreased from 2.7 +/- 0.7 to 0.7 +/- 0.7 (p < 0.001). CONCLUSION: MARS treatment led in all patients to an improvement of clinical, hemodynamic and neurological conditions, with significant reduction in the hepatic toxins blood level. Treatment biocompatibility and tolerance were satisfactory.

Acute Kidney Injury↗

PubMed2000

Bile acids in porcine fetal bile.

A study of the biliary bile acid composition in porcine fetus compared with that of the adult pig is described. Biles, collected during gestation (weeks 4, 15 to 17 and at birth), aged six months and two years old, were analyzed by gas-liquid chromatography and capillary GC-MS. Bile acids were separated into different conjugate groups by chromatography on the lipophilic anion exchange gel, piperidinohydroxypropyl Sephadex LH-20. All and one fourth of the total bile acids in the bile of weeks 4 and 15 of gestation, respectively, were present as unconjugated form, however, only a trace of unconjugated bile acids was present in bile of late gestation, the young and the adult pigs. The ratio of glycine/taurine (G/T) conjugates in the conjugated fraction of the fetal bile at 15 weeks gestation was less than 1, which markedly contrasted with the conjugation pattern for adult bile where the ratio of G/T conjugates was approximately more than 9. The predominant acids identified in porcine fetal bile of the 4 weeks gestation were cholic acid (3alpha,7alpha,12alpha-trihydroxy-5beta-chola n-24-oic acid) and chenodeoxycholic acid (3alpha,7alpha -dihydroxy-5beta-cholan-24-oic acid). However, cholic acid in late gestation, young, and adult bile was the smallest component, whereas chenodeoxycholic acid was still the major constituent of these biles. The presence of small but valuable amounts of allocholic acid (3alpha,7alpha,12alpha-trihydroxy-5alpha-chol an-24-oic acid) and cholic acid in early gestation suggested the presence of 12alpha-hydroxylase activity of steroid nucleus in fetal liver. Considerable amounts of glycine-conjugated hyodeoxycholic acid were found in the bile of the gestation periods, suggesting the placental transfer of this bile acid from maternal circulation.

Aging↗

PubMed1981

Effect of bile duct ligation on bile acid metabolism in rats.

The effect of bile duct ligation on the quantitative and qualitative changes of bile acids in serum, liver, urine, and feces, and the concentration of cholesterol and phospholipids in serum and liver were examined in male rats. The concentration of bile acids in serum increased over 100-fold on day 5 but was lower than the 5-day level on days 10 and 15. The concentration in the liver also increased about 10-fold. beta-Muricholic acid predominantly increased but the secondary bile acids, deoxycholic acid and hyodeoxycholic acid, decreased. The urinary excretion of bile acids increased to about 40 mg/day per rat on the first day of bile duct ligation but this increase was reduced on day 2 to about half and remained at that level until day 24. These values exceeded that of fecal bile acids, 12 mg/day per rat, before bile duct ligation. The amount of bile acid sulfates in the urine was as low as 1% of the total. The urinary non-sulfated bile acids consisted mainly of beta-muricholic acid (60%) and cholic acid (20%), while the sulfates contained a considerable amount of unidentified acidic substances (40%) in addition to cholic acid and beta-muricholic acid. The concentration of cholesterol and phospholipids in serum markedly increased on day 5 but declined gradually thereafter. The liver cholesterol concentration did not change but the phospholipid concentration decreased. Fecal sterols did not change in both the total amount and composition. These data indicated that daily synthesis of bile acids, especially beta-muricholic acid, was accelerated in bile duct-ligated rats.

Animals↗

PubMed1983

Effect of bile acid feeding on hepatic steroid 12 alpha-hydroxylase activity in hamsters.

The effects of feeding cholic acid, chenodeoxycholic acid and ursodeoxycholic acid on the activity of the hepatic steroid 12 alpha-hydroxylase, gallbladder bile acid composition, fecal neutral sterol output, cholesterol synthesis and bile acid synthesis were determined in female hamsters. The 12 alpha-hydroxylase activity was inhibited to 56% by cholic acid, to 62% by chenodeoxycholic acid, and to 78% by ursodeoxycholic acid compared with the control. Bile acid composition was altered by feeding of cholic acid and chenodeoxycholic acid to be rich in the given bile acids. Fecal neutral sterol output increased about twice by feeding chenodeoxycholic acid and ursodeoxycholic acid, whereas cholic acid had no significant effect. Body cholesterol synthesis increased to 217% by chenodeoxycholic acid and to 274% by ursodeoxycholic acid, whereas effect of cholic acid was not significant. Bile acid synthesis was suppressed to 48% of control only by chenodeoxycholic acid. A positive correlation between the 12 alpha-hydroxylase activity and the bile acid synthesis was observed in the control, chenodeoxycholate-fed and ursodeoxycholate-fed animals. In conclusion, ursodeoxycholic acid might have less inhibitory effect on the steroid 12 alpha-hydroxylase and the bile acid synthesis than chenodeoxycholic acid.

Animals↗

PubMed2002

[Features of composition of bile acids in duodenal bile in patients with chronic pancreatitis].

A number of conditions contributing to changes in metabolism of bile acids (BA) appears in case of chronic pancreatitis (CP). There was a study of particular features of the BA composition in the bile of 20 patients with CP and 10 donors with the help of the thin-layer chromatography method. The first group consisted of patients with alcoholic pancreatitis (AP) at the acute stage of the disease, and the second one consisted of patients with chronic biliary pancreatitis. A substantial increase in the content of conjugated BA was recorded in the bile of AP patients. The dependence of changes of bile secretion and its content on the duration of the disease was established. A reduction of bile secretion and decrease in the content of conjugated BA and cholesterol therein were recorded in the second group of patients. A particular feature of the BA composition was a decrease in the percentage of conjugates of cholic acid and glycodioxicholan acids. Cholic acid prevailed among free BAs. The lithocholic acid content increased depending on the duration and severity of the disease. Possible reasons of cholesterol deficit and high free cholic acid content in the bile of CP patients were noted. The findings indicate a colloidal stability of the bile in case of CP. An abnormal conjugation of BAs with glycine and especially with taurine can be not only the reason for changes in the qualitative BA composition but can also lead to changes in absorption of exogenous cholesterol. These changes are most apparent in patients with biliary-dependent forms of pancreatitis.

Adult↗

PubMed1990

Dose response to a dietary oat bran fraction in cholesterol-fed rats.

The two objectives of this research were to improve the cholesterol-fed rat as a model for evaluating the hypocholesterolemic potential of foods and to determine the relationship between serum and liver lipid levels in the cholesterol-fed rat and the ingestion of nine levels of a high fiber oat flour (HFOF) derived from oat bran. Ingestion of 0.2% cholic acid, sodium cholate or sodium taurocholate with 1% cholesterol (CH) significantly elevated serum and liver CH, liver triglycerides and liver weight compared to those values in control rats fed diets not containing CH and bile acids; 0.05 and 0.1% cholic acid with 1% CH were also effective. Ingestion of increasing amounts of HFOF, containing 0-10% dietary fiber, by rats made hypercholesterolemic with 1% CH and 0.1% cholic acid in the diet produced a significant inverse relationship between serum and liver cholesterol levels and HFOF intake; r = 0.48, p less than 0.0001 for serum CH and r = 0.55, p less than 0.0001 for liver CH. Because of the similarities in the responses of humans and of the cholesterol-fed rat to oat fiber ingestion, this dose-response relationship in the rat model suggests that larger intakes of soluble oat fiber sources may be accompanied by greater reduction in serum CH levels in humans.

Animals↗

PubMed1994

The effect of bile acids and piroxicam on MHC antigen expression in rat colonocytes during colon cancer development.

The effect of bile acids and piroxicam on the expression of major histocompatibility complex (MHC) antigens in colonocytes was evaluated in rats treated with the colonic carcinogen azoxymethane (AOM). Male Fischer-344 rats were fed a basal diet (AIN-76) supplemented with 0.4% cholic acid, 0.4% ursodeoxycholic acid, 0.2% ursodeoxycholic acid plus 0.2% cholic acid, or 75 p.p.m. piroxicam. Rats were injected subcutaneously once a week for 2 weeks with AOM (15 mg/kg body weight/week) or vehicle, after being fed their respective diets for two weeks. The rats were killed at 16 weeks, while parallel identical groups of rats were killed at 28 weeks, and colon tumours were counted. None of the rats treated with AOM-vehicle developed tumours at 28 weeks, while in the AOM-treated rats the frequency of colonic tumours was as follows: AOM alone 50%, cholic acid 74%, ursodeoxycholic acid 17%, piroxicam 28%, ursodeoxycholic plus cholic acid 46%. The expression of RT1A, RT1B and RT1D was determined in isolated colonocytes by immune fluocytometry. Normal rat colonocytes express all three MHC antigens strongly. Neither the bile acids nor piroxicam affected MHC antigen expression in AOM-vehicle-treated rats. AOM did not effect MHC antigen expression compared to normal controls. Cholic acid had no significant effect on the expression of MHC antigens in AOM-treated rats. Ursodeoxycholic acid alone or in combination with cholic acid increased the expression of RT1A compared to normal controls, of RT1B compared to AOM-treated rats, and of RT1D compared to controls or AOM-treated rats. Piroxicam increased the expression of all three antigens compared to either control or AOM-treated rats. These findings indicate that (1) ursodeoxycholic acid and piroxicam up-regulate colonic MHC antigen expression in the AOM model of colonic carcinogenesis; (2) the colon of rats exposed to AOM responds differently than the normal colon with respect to MHC regulation; and (3) the protective effect of ursodeoxycholic acid and piroxicam on colon tumour formation seems to be paralleled by an increase in MHC antigen expression.

Animals↗

PubMed1985

Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26.

To examine the defect in side-chain oxidation during the formation of bile acids in cerebrotendinous xanthomatosis, we measured in vitro hepatic microsomal hydroxylations at C-12 and C-25 and mitochondrial hydroxylation at C-26 and related them to the pool size and synthesis rates of cholic acid and chenodeoxycholic acid as determined by the isotope dilution technique. Hepatic microsomes and mitochondria were prepared from seven subjects with cerebrotendinous xanthomatosis and five controls. Primary bile acid synthesis was markedly reduced in cerebrotendinous xanthomatosis as follows: cholic acid, 133 +/- 30 vs. 260 +/- 60 mg/d in controls; and chenodeoxycholic acid, 22 +/- 10 vs. 150 +/- 30 mg/d in controls. As postulated for chenodeoxycholic acid synthesis, mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha-diol was present in all specimens and was 30-fold more active than the corresponding microsomal 25-hydroxylation. However, mean mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha-diol was less active in cerebrotendinous xanthomatosis than in controls: 59 +/- 17 compared with 126 +/- 21 pmol/mg protein per min. As for cholic acid synthesis, microsomal 25-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was substantially higher in cerebrotendinous xanthomatosis and control preparations (620 +/- 103 and 515 +/- 64 pmol/mg protein per min, respectively) than the corresponding control mitochondrial 26-hydroxylation of the same substrate (165 +/- 25 pmol/mg protein per min). Moreover in cerebrotendinous xanthomatosis, mitochondrial 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol-26-hydroxylase activity was one-seventh as great as in controls. Hepatic microsomal 12 alpha-hydroxylation, which may be rate-controlling for the cholic acid pathway, was three times more active in cerebrotendinous xanthomatosis than in controls: 1,600 vs. 500 pmol/mg protein per min. These results demonstrate severely depressed primary bile acid synthesis in cerebrotendinous xanthomatosis with a reduction in chenodeoxycholic acid formation and pool size disproportionately greater than that for cholic acid. The deficiency of chenodeoxycholic acid can be accounted for by hyperactive microsomal 12 alpha-hydroxylation that diverts precursors into the cholic acid pathway combined with decreased side-chain oxidation (mitochondrial 26-hydroxylation). However, side-chain oxidation in cholic acid biosynthesis may be initiated via microsomal 25-hydroxylation of 5beta-cholestane-3alpha,7alpha,12alpha-triol was substantially lower in control and cerebrotendinous xanthomatosis liver. Thus, separate mechanisms may exist for the cleavage of the cholesterol side chain in cholic acid and chenodeoxycholic acid biosynthesis.

Adult↗

PubMed1998

Extrahepatic deposition and cytotoxicity of lithocholic acid: studies in two hamster models of hepatic failure and in cultured human fibroblasts.

Effects of bile acids on tissues outside of the enterohepatic circulation may be of major pathophysiological significance under conditions of elevated serum bile acid concentrations, such as in hepatobiliary disease. Two hamster models of hepatic failure, namely functional hepatectomy (HepX), and 2-day bile duct ligation (BDL), as well as cultured human fibroblasts, were used to study the comparative tissue uptake, distribution, and cytotoxicity of lithocholic acid (LCA) in relation to various experimental conditions, such as binding of LCA to low-density lipoprotein (LDL) or albumin as protein carriers. Fifteen minutes after i.v. infusion of [24-(14)C]LCA, the majority of LCA in sham-operated control animals was recovered in liver, bile, and small intestine. After hepatectomy, a significant increase in LCA was found in blood, muscle, heart, brain, adrenals, and thymus. In bile duct-ligated animals, significantly more LCA was associated with blood and skin, and a greater than twofold increase in LCA was observed in the colon. In the hepatectomized model, the administration of LCA bound to LDL resulted in a significantly higher uptake in the kidneys and skin. The comparative time- and concentration-dependent uptake of [14C]LCA, [14C]chenodeoxycholic acid (CDCA), and [14C]cholic acid (CA) in cultured human fibroblasts was nonsaturable and remained a function of concentration. Initial rates of uptake were significantly increased by approximately tenfold, with decreasing hydroxylation of the respective bile acid. After 1 hour of exposure of fibroblasts to LCA, there was a significant, dose-dependent decrease in mitochondrial dehydrogenase activity from 18% to 34% of the control, at LCA concentrations ranging from 1 to 20 micromol/L. At a respective concentration of 100 and 700 micromol/L, CDCA caused a 35% and 99% inhibition of mitochondrial dehydrogenase activity. None of the bile acids tested, with the exception of 700 micromol/L CDCA, caused a significant release of cytosolic lactate dehydrogenase into the medium. In conclusion, we show that bile acids selectively accumulate in nonhepatic tissues under two conditions of impaired liver function. Furthermore, the extrahepatic tissue distribution of bile acids during cholestasis may be affected by serum lipoprotein composition. At a respective concentration of 1 and 100 micromol/L, LCA and CDCA induced mitochondrial damage in human fibroblasts, after just 1 hour of exposure. Therefore, enhanced extrahepatic uptake of hydrophobic bile acids during liver dysfunction, or disorders of lipoprotein metabolism, may have important implications for bile-acid induced cytotoxic effects in tissues of the systemic circulation.

Alanine Transaminase↗

PubMed1995

Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids.

BACKGROUND & AIMS: The mechanisms causing liver injury in cholestatic diseases are unclear. The hypothesis that accumulation of hydrophobic bile acids in hepatocytes during cholestasis leads to generation of oxygen free radicals and oxidative injury was tested. The aim of this study was to determine if hydrophobic bile acid toxicity is associated with increased hydroperoxide generation in isolated rat hepatocytes and mitochondria. METHODS: Hepatocytes were exposed to taurochenodeoxycholic acid (TCDC; 0-2000 mumol/L) or taurocholic acid (TC; 1000 mumol/L), and cellular injury, intracellular hydroperoxide generation, and thiobarbituric acid-reacting substances (TBARS) were measured. Isolated mitochondria were incubated with 400 mumol/L chenodeoxycholic acid or 400 mumol/L cholic acid, and hydroperoxide generation was measured fluorometrically. RESULTS: Hepatocyte injury, hydroperoxide generation, and TBARS increased over 4 hours on exposure to TCDC but not TC. Hydroperoxide generation preceded hepatocyte injury and accumulation of TBARS. Preincubation of hepatocytes with the antioxidant, d-alpha-tocopheryl succinate, completely abrogated cellular injury, hydroperoxide, and TBARS generation. Hydroperoxide generation was increased in mitochondria exposed to chenodeoxycholic acid. CONCLUSIONS: Intracellular generation of hydroperoxides by mitochondria appears to be an early event in hydrophobic bile acid-induced hepatocyte toxicity. Antioxidants may be of benefit in cholestasis.

Animals↗