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PubMed1983

Influence of bile acids on cholera toxin-induced secretion in mouse jejunum.

The influence of bile acids on intestinal secretion induced by cholera toxin (CT) was studied in mice. The secretion was examined in ligated loops after the bile flow had been stopped by ligation of the common bile duct (CD). Bile depletion was found to inhibit both the secretion induced by CT, the degradation of CT, and the binding of CT to epithelial cells--all of which could be restored to normal by the application, before CT challenge, of bile acids in the loops of CD-ligated mice. Out of the nine bile acids tested, cholic acid, deoxycholic acid and chenodeoxycholic acid were the most potent, their ED50 values being 0.2, 0.2, and 0.6 mM respectively.

Animals↗

PubMed1980

Effect of bile acid perfusion on colonic motor function in patients with the irritable colon syndrome.

A study was performed to determine the effect of bile acid perfusion on motility in the sigmoid colon of patients with the irritable colon syndrome compared with normal subjects. Deoxycholic acid (15 mM) statistically significantly increased motility in normal subjects (control 25.0 +/- 6.4%, perfusion 71.4 +/- 7.2%, P < 0.05) but neither chenodeoxycholic acid nor cholic acid had any apparent effect. In patients with the irritable colon syndrome, however, deoxycholic acid at 5 mM concentration (control 29.8 +/- 4.2%, during perfusion 57.4 +/- 6.5%, P < 0.05) as well as at 15 mM concentration (control 19.4 +/- 5.7+, perfusion 57.8 +/- 9.6%, P < 0.05) statistically significantly increased rectosigmoid motility. Patients with the irritable colon syndrome had a high resting 0.033-0.066 Hz (2-4 c/m) electrical activity, whereas in normal subjects 0.1-0.15 Hz (6-9 c/m) activity was greater. However, there was no statistically significant alteration in either electrical rhythm during the period of bile acid perfusion. In conclusion, additional evidence is presented to suggest that deoxycholic acid is the only bile acid likely to be implicated in the motor disorder of the irritable colon syndrome.

Bile Acids and Salts↗

PubMed1987

Oxidation of primary bile acids by a 7 alpha-hydroxysteroid dehydrogenase elaborating Clostridium bifermentans soil isolate.

A gram-positive, rod-shaped anaerobe (strain F-6) was isolated from soil. This organism was identified by cellular morphology as well as fermentative and biochemical data as Clostridium bifermentans. Strain F-6 formed 7-ketolithocholic acid from chenodeoxycholic acid and 7-ketodeoxycholic acid from cholic acid in whole cell cultures, but did not transform deoxycholic acid, ursodeoxycholic acid, or ursocholic acid. This reaction is reversible. The structures of 7-ketolithocholic acid and 7-ketodeoxycholic acid were verified by mass spectroscopy and by thin-layer chromatography using Komarowsky's spray reagent. When incubated with the strain F-6 glycine and taurine conjugates of the primary bile acids were partially hydrolyzed and transformed to 7-keto products. Optimal yields of 7-ketolithocholic acid and 7-ketodeoxycholic acid were obtained after 78 h of incubation. Culture pH changed with time and was characterized by an initial drop (1.1 pH units) and a gradual increase back to the starting pH (7.3). Corroborating these observations, an inducible, NADP-dependent, 7 alpha-hydroxysteroid dehydrogenase was demonstrated in cell extracts of strain F-6. A trace of NAD-dependent 7 alpha-hydroxysteroid dehydrogenase was also found. A substantial increase in the specific activity of the NADP-dependent 7 alpha-hydroxysteroid dehydrogenase was observed when either 7-ketolithocholic acid, chenodeoxycholic acid, or deoxycholic acid was included in the growth medium. Optimal induction of the NADP-dependent 7 alpha-hydroxysteroid dehydrogenase was achieved with 0.3-0.4 mM 7-ketolithocholic acid. Production of the enzyme(s) was optimal at 6-8 h of growth and the 7 alpha-hydroxysteroid dehydrogenases had a pH optimum of approximately 11.(ABSTRACT TRUNCATED AT 250 WORDS)

Bile Acids and Salts↗

PubMed2005

FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade.

The regulation of the rabbit apical sodium-dependent bile acid transporter (ASBT) was studied both in vivo and in vitro. New Zealand White rabbits were fed 0.5% deoxycholic acid (DCA) or SC-435, a competitive ASBT inhibitor, for 1 wk. In DCA-fed rabbits, ASBT expression was repressed, associated with activated FXR, and evidenced by increased ileal short heterodimer partner (SHP) mRNA. Feeding SC-435 to the rabbits blocked bile acid absorption, decreased SHP mRNA, and increased ASBT expression. A 1.9-kb rabbit ASBT 5'-flanking region (promoter) was cloned, and a cis-acting element for alpha-fetoprotein transcription factor (FTF) was identified (-1166/-1158). The effects of transcriptional factors and different bile acids on the rabbit ASBT promoter were studied in Caco-2 cells. FTF stimulated the rabbit ASBT promoter activity fourfold but not after the FTF binding site was deleted from the promoter. Increasing the SHP protein notably inhibited FTF-dependent trans-activation of rabbit ASBT. Adding hydrophobic bile acids deoxycholic acid, chenodeoxycholic acid, and cholic acid, activating ligands for FXR, inhibited rabbit ASBT promoter activity in Caco-2 cells, but this inhibitory effect was abolished after the FTF binding site was deleted. Ursodeoxycholic acid and ursocholic acid, nonactivating ligands for FXR, did not repress ASBT promoter activity. Thus the rabbit ASBT promoter is negative-feedback regulated by bile acids via a functional FTF binding site. Only FXR-activating ligands can downregulate rabbit ASBT expression through the regulatory cascade FXR-SHP-FTF.

Animals↗

PubMed1982

Bile acid transport in cultured rat hepatocytes.

The mechanisms of bile acid uptake have been studied with primary monolayer cultures of rat hepatocytes. Hepatocytes were incubated with taurocholic acid (TC), glycocholic acid (GC), cholic acid (CA), glycochenodeoxycholic acid (GCDC), chenodeoxycholic acid (CDCA), deoxycholic acid (DOCA), lithocholic acid (LCA), or cholylglycylhistamine (CCH), a neutral bile acid derivative for 10 s to 60 min in medium containing sodium chloride, sodium chloride with 1 mM ouabain, or choline chloride. Cells were washed free of radioactive tracer, cell-associated radioactivity was quantitated, and bile acid uptake rates, kinetic parameters of uptake, and steady-state bile acid content were calculated. Two mechanisms for bile acid uptake were identified. Uptake of TC, GC, CA, and GCDC occurred predominantly via a sodium-dependent, ouabain-suppressible saturable mechanism, presumably sodium-coupled transport. Estimates of apparent Km and Vmax for these bile acids were TC, 33 micro M and 0.36 nmol . min-1 . mg prot-1; GC, 18 micro M and 0.22 nmol . min-1 . mg prot-1; CA, 13 micro M and 0.10 nmol . min-1 . mg prot; and GCDC, 6 micro M and 0.21 nmol . min-1 . mg prot, respectively. Uptake via this sodium-coupled mechanism exhibited considerable substrate selectivity. It was enhanced by increased ring hydroxylation and amino acid conjugation and decreased by further conjugation with a neutral histamine group (CGH). In contrast, uptake of CDCA, DOCA, LCA, and CGH occurred primarily via a nonsaturable sodium-independent mechanism, possibly simple diffusion. This mechanism accounted for only a small portion of uptake of TC, GC, CA, and GCDC at low bile acid concentrations. Nonsaturable bile acid uptake rates appeared to correlate with decane-buffer partition coefficients and to be related to bile acid structure.

Animals↗

PubMed1994

Expression and characterization of a functional rat liver Na+ bile acid cotransport system in COS-7 cells.

A cDNA for the rat liver sodium-dependent bile acid cotransporter was expressed in COS-7 cells to study the functional properties of the translated protein in a mammalian cell line. A 1.2-kb insert was ligated into a pMAMneo vector and transiently transfected using electroporation. After optimal conditions were established, the transiently transfected COS cells were screened with fluorescent-conjugated labeled bile acids for evidence of expression of the cotransporter after 48 h. The uptake of [3H]taurocholate ([3H]TC) was then determined in cells transfected with or without the bile acid insert. Progressive uptake of [3H]TC (0.45 microM) was observed for 30 min in the presence of sodium. In contrast, no uptake of [3H]TC was observed in the absence of sodium, in nontransfected COS cells, or in COS cells transfected with the empty plasmid. Kinetic studies revealed a Michaelis constant (Km) of 29 microM, essentially identical to the Km of this cotransporter described in intact rat hepatocytes and membrane vesicles. Uptake of [3H]TC (5.0 microM) at 5 min (n = 3-6) was inhibited by 100 microM taurochenodeoxycholic acid (81%), tauroursodeoxycholic acid (77%), cholic acid (55%), chenodeoxycholic acid (74%), and ursodeoxycholic acid (56%) but not by 100 microM taurodehydrocholate, 1 mM probenecid, or 100 microM bilirubin. In contrast, bumetanide (500 microM) inhibited [3H]TC uptake by 52%. These studies indicate that the isolated cDNA codes for a physiological bile acid transporter present in rat hepatocytes and that posttranslational factors present in mammalian cells may not be as important in defining properties of this cotransport system.

Animals↗

PubMed1994

Variation of serum bile acids in patients with colorectal adenomas during a one-year follow-up.

We were recently able to show that patients with colorectal adenomas have an increased serum level of the secondary bile acid deoxycholic acid [Bayerdörffer et al.: Gastroenterology 1993; 104:145-151]. The course of individual serum bile acids was followed for 1 year in a random subgroup of these patients. The individual serum bile acids of 39 patients, 10 men with adenoma, 12 men without adenoma, 8 women with adenoma, and 9 women without adenoma, were determined at 6-month intervals by gas liquid chromatography (GC). The mean individual differences in serum bile acids between baseline and 6-month follow-up and baseline and 12-month follow-up ranged from +19 to -15 nmol/l in men with adenoma, and from +66 to -64 nmol/l in men without adenoma. In women, the ranges were +73 to -74 nmol/l in those with adenoma and +33 to -81 nmol/l in those without adenoma. The variations of the relative percentages of the individual bile acids in the three investigations were lower than those of the absolute values. The differences between the baseline, the 6-month, and the 12-month follow-up were not significant for the major bile acids deoxycholic acid, chenodeoxycholic acid and cholic acid. The main finding, namely an increase in the serum levels and the relative proportion of deoxycholic acid in men with colorectal adenomas remained unchanged throughout the follow-up. The data indicate that measurement of the bile acid pattern by GC is a useful and reproducible parameter in investigating the role of secondary bile acids in the pathogenesis of colorectal cancer.

Adenoma↗

PubMed2003

Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation.

The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that plays a major role in bile acid and cholesterol metabolism. To obtain an insight into the structure-activity relationships of FXR ligands, we investigated the functional roles of structural elements in the physiological ligands chenodeoxycholic acid [CDCA; (3alpha,7alpha)], cholic acid [CA; (3alpha,7alpha,12alpha)], deoxycholic acid [DCA; (3alpha,12alpha)], and lithocholic acid (3alpha) in regard to FXR activation in a cell-based FXR response element-driven luciferase assay and an in vitro coactivator association assay. Conversion of the carboxyl group of CDCA or CA to an alcohol did not greatly diminish their ability to activate FXR. In contrast, the 7beta-epimers of the alcohols were inactive, indicating that the bile alcohols retained the ligand properties of the original bile acids and that the 7beta-hydroxyl group diminished their FXR-activating effect. Similarly, hydroxyl epimers of DCA exhibited decreased activity compared with DCA, indicating a negative effect of 3beta- or 12beta-hydroxyl groups. Introduction of an alkyl group at the 7beta- or 3beta-position of CDCA resulted in diminished FXR activation in the following order of alkyl groups: 7-ethyl=7-propyl>3-methyl>7-methyl. These results indicate that bulky substituents, whether hydroxyl groups or alkyl residues, at the beta-position of cholanoids decrease their ability to activate FXR.

Bile Acids and Salts↗

PubMed2006

Transport of fluorescent chenodeoxycholic acid via the human organic anion transporters OATP1B1 and OATP1B3.

This study sought to clarify the contributions of organic anion-transporting polypeptide (OATP) 1B1 and 1B3 to the liver uptake of chenodeoxycholic acid (CDCA). We synthesized a fluorescent version of CDCA, chenodeoxychilyl-(Nepsilon-NBD)-lysine (CDCA-NBD), to characterize transporter-mediated uptake. CDCA-NBD is efficiently transported by OATP1B1 and OATP1B3 with high affinities. The Michaelis-Menten constants for CDCA-NBD uptake by OATP1B1 and OATP1B3 were 1.45 +/- 0.39 microM and 0.54 +/- 0.09 microM, respectively. By confocal laser scanning microscopy, CDCA-NBD, which is taken up by OATP1B1 and OATP1B3, was observed to localize to the cytosol. We also examined the transport of newly synthesized fluorescent bile acids. NBD-labeled bile acids, including cholic acid, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid, were all transported by OATP1B1 and OATP1B3. CDCA-NBD exhibited the highest rate of transport of the five NBD-labeled bile acids examined in OATP1B1- and OATP1B3-expressing cells. Our results suggest that OATP1B1 and OATP1B3 play important roles in CDCA uptake into the liver. Fluorescent bile acids are useful tools to characterize the uptake properties of membrane transporters.

Bile Acids and Salts↗

PubMed1995

Growth hormone treatment does not alter biliary lipid metabolism in healthy adult men.

GH is important for the hepatic low density lipoprotein (LDL) receptor induction that occurs after estrogen treatment. GH treatment increases liver LDL receptors and lowers plasma LDL cholesterol in man. Estrogen treatment enhances biliary secretion of cholesterol, resulting in supersaturation of bile and an increased risk of gallstone formation. The present study was undertaken to investigate whether GH treatment also influences biliary lipid metabolism in humans. Twelve healthy male volunteers (mean age, 31 +/- 1 yr) were studied before and during the third week of treatment with recombinant human GH (0.1 IU/kg.day). Plasma lipids, bile acid kinetics, and biliary lipid composition were monitored. Plasma total and LDL cholesterol levels were reduced by 10% in response to therapy. However, no significant changes were observed in the biliary lipid composition or cholesterol saturation of gallbladder bile. Furthermore, there were no changes in chenodeoxycholic acid or cholic acid kinetics. The reduction of plasma LDL cholesterol in response to GH treatment in healthy adult men is not associated with detectable changes in biliary lipid metabolism. Thus, in contrast to estrogen, GH therapy of adults probably does not result in an increased risk of cholesterol gallstone development.

Adult↗

PubMed2003

The small heterodimer partner interacts with the pregnane X receptor and represses its transcriptional activity.

SHP (small heterodimer partner, NR1I0) is an atypical orphan member of the nuclear receptor subfamily in that it lacks a DNA-binding domain. It is mostly expressed in the liver, where it binds to and inhibits the function of nuclear receptors. SHP is up-regulated by primary bile acids, through the activation of their receptor farnesoid X receptor, leading to the repression of cholesterol 7alpha-hydroxylase (CYP7alpha) expression, the rate-limiting enzyme in bile acid production from cholesterol. PXR (pregnane X receptor, NR1I2) is a broad-specificity sensor that recognizes a wide variety of synthetic drugs as well as endogenous compounds such as bile acid precursors. Upon activation, PXR induces CYP3A and inhibits CYP7alpha, suggesting that PXR can act on both bile acid synthesis and elimination. Indeed, CYP7alpha and CYP3A are involved in biochemical pathways leading to cholesterol conversion into primary bile acids, whereas CYP3A is also involved in the detoxification of toxic secondary bile acid derivatives. Here, we show that PXR is a target for SHP. Using pull-down assays, we show that SHP interacts with both murine and human PXR in a ligand-dependent manner. From transient transfection assays, SHP is shown to be a potent repressor of PXR transactivation. Furthermore, we report that chenodeoxycholic acid and cholic acid, two farnesoid X receptor ligands, induce up-regulation of SHP and provoke a repression of PXR-mediated CYP3A induction in human hepatocytes as well as in vivo in mice. These results reveal an elaborate regulatory cascade, tightly controlled by SHP, for both the maintenance of bile acid production and detoxification in the liver.

Animals↗

PubMed1986

Kinetic evidence for a common transport route of benzylpenicillin and probenecid by freshly prepared hepatocytes in rats. Influence of sodium ion, organic anions, amino acids and peptides on benzylpenicillin uptake.

Hepatic transport system of benzylpenicillin was characterized by using freshly prepared rat hepatocytes. Uptake of benzylpenicillin and cefpiramide did not require the presence of sodium ion in the incubation medium. No influence of several kinds of amino acids (leucine, histidine, phenylalanine, valine, alanine, glutamic acid and glycine) and peptides (prolyl-leucine, glycyl-glycine, glycyl-sarcosine, glycyl-leucine and gamma-glutamyl-cysteinylglycine) was observed for benzylpenicillin uptake into hepatocytes. Taurocholic acid and cholic acid significantly inhibited benzylpenicillin uptake. The kinetic study revealed that taurocholic acid inhibited benzylpenicillin uptake in a noncompetitive fashion. A similar effect of benzylpenicillin on taurocholic acid uptake was observed, suggesting that the affinity site of the hepatic transport carrier of benzylpenicillin is distinct from that of taurocholic acid. It is noteworthy that p-aminohippuric acid and p-acetylaminohippuric acid did not inhibit benzylpenicillin uptake. In contrast to the mutual inhibition behavior of benzylpenicillin and taurocholic acid, benzylpenicillin is fully and competitively inhibited by the simultaneous addition of probenecid. The inhibition constant Ki value of probenecid was calculated to be 0.322 mM. The uptake of probenecid was also significantly inhibited by benzylpenicillin. It is postulated that the affinity site of benzylpenicillin transport carrier is the same as that of probenecid and that the whole process of the benzylpenicillin transport system is common, at least in part, to the probenecid transport process in the liver.

Amino Acids↗

PubMed2000

Bile acid metabolism, bacterial bowel flora and intestinal function following ileal pouch-anal anastomosis in dogs, with reference to the influence of administration of ursodeoxycholic acid.

The pathophysiology following a total colectomy with ileal pouch-anal anastomosis (IPAA) has not been sufficiently clarified yet. We investigated bile acid metabolism, bacterial bowel flora and transit of the alimentary tract after IPAA, with reference to administration of ursodeoxycholic acid (UDCA) in dogs undergoing IPAA. Ten adult beagle dogs underwent IPAA at one stage, and were observed for 12 months. UDCA (100 mg/day) was administered orally to five dogs, and the other five did not. In the UDCA(+) group, UDCA replaced other bile acids, especially cholic acid, accounting for 16.5% of gallbladder bile at 12 months after surgery. Both plasma levels and postprandial increase of total bile acids remained unchanged in the UDCA(+) group, but decreased in the UDCA(-) group at 12 months. Fecal excretion of bile acids tended to be smaller in the UDCA(+) group, and the ratio of secondary to primary bile acids was larger in the UDCA(-) group. Almost all the bile acids were in free form in stool, and UDCA constituted 19% in the UDCA(+) group. The transit time of the whole alimentary tract was elongated by administering UDCA, especially at an early period after IPAA. Although both anaerobic and aerobic bacteria decreased after IPAA, the latter decreased more in stool, resulting in an increase in the ratio of total anaerobes/total aerobes, especially in the UDCA(-) group. The decrease in Bacteroidaceae and Lactobacillus after IPAA was slightly smaller in the UDCA(+) group. Administration of UDCA following IPAA was efficient to induce rapid intestinal adaptation and also to keep the bile acid fraction in the ileal pouch less harmful.

Administration, Oral↗

PubMed1980

Evaluation of enzymic and radioimmunoassay methods for measuring serum bile acids.

Serum bile acids were measured in control subjects and in 23 patients with cirrhosis or cholestasis using an enzymic method which measures total non-sulphated bile acids and 2 commercially available radioimmunoassay methods which measure cholylglycine (CG) and sulpholithocholylglycine (SLCG) respectively. All 3 methods gave abnormal values in patients with cholestasis. In cirrhosis the CG method gave abnormal values more often than the enzymic method. The SLCG method was much less sensitive. Measurement of CG in 2 postprandial samples per patient detected only one patient with normal fasting but abnormal postprandial levels. Analysis of samples by gas liquid chromatography (GLC) showed that the enzymic and CG methods gave a good estimation of total non-sulphated bile acids and cholic acid respectively. Values determined by the SLCG method were much higher than the equivalent GLC values. The CG method is faster than the enzymic method and is less expensive provided sample are analysed in sufficiently large batches.

Bile Acids and Salts↗

PubMed1985

Fasting and postprandial serum bile acid concentration with special reference to variations in the conjugate profile.

Serum bile acids were group-separated by ion exchange chromatography on diethylaminohydroxypropyl Sephadex LH-20 into unconjugated bile acids and bile acids conjugated with either glycine, taurine, glucuronic acid or sulphuric acid. The conjugate moiety was hydrolysed by treatment with a combination of Helix pomatia and cholylglycine hydrolase and the released bile acids analysed by gas liquid chromatography/mass spectrometry. Analysis of fasting and postprandial serum from six healthy subjects showed that, in addition to the primary bile acids, cholic (C) and chenodeoxycholic acid (CDC), secondary bile acids were present to varying extents. Unconjugated serum bile acids were found in four of the six subjects. Glycine and taurine conjugates of C and CDC and their glucuronides and sulphates were found in all subjects. The postprandial increase of serum bile acids was mainly due to increase of the glycine conjugates of C and CDC. After the meal, the ratio C:CDC in glycine and taurine conjugates shifted to lower values.

Adult↗

PubMed1988

Transport of serum bile acids in patients with liver cirrhosis and hyperbilirubinaemia.

From 12 patients with liver cirrhosis and hyperbilirubinaemia, the different conjugates of bilirubin and bile acids in the serum were separated and determined. The serum of the patients contained varying amounts of unconjugated bilirubin, which was not correlated to total serum bilirubin. No correlation between bilirubin conjugates and different conjugates of bile acids could be found, indicating different elimination processes for these substances. To examine whether a changed plasma transport of bile acids, which may contribute to the different excretion pattern of bilirubin and bile acids, occurs in liver cirrhosis, the bile acids in the different serum lipoprotein fractions were determined in seven of the patients. It was found that 40% of serum bile acids were bound to serum lipoproteins, despite decreased serum lipoprotein levels. The degree of lipoprotein binding of bile acids was not correlated to total serum bile acid concentrations. Cholic acid conjugates were present to a higher extent in the lipoprotein fractions than those of chenodeoxycholic acid or of deoxycholic acid. Determination was made of the distribution of individual conjugates between different lipoproteins and it was found that most of the glycine conjugates were present in high density lipoprotein, whereas the main part of sulphates and taurine conjugates were present in low density lipoprotein. These results indicate that a higher fraction of bile acids in liver cirrhosis is transported by lipoproteins in plasma, which may be of importance for the hepatic elimination of bile acids in cases with this disease.

Adult↗

PubMed2005

Bile salts inhibit growth and induce apoptosis of human esophageal cancer cell line.

AIM: To explore the effect of six bile salts, including glycocholate (GC), glycochenodeoxycholate (GCDC), glycodeoxycholate (GDC), taurocholate (TC), taurochenodeoxycholate (TCDC), taurodeoxycholate (TDC), and two bile acids including cholic acid (CA) and deoxycholic acid (DCA) on esophageal cancer Eca109 cell line. METHODS: Eca109 cells were exposed to six bile salts, two bile acids and the mixed bile salts at different concentrations for 24-72 h. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to detect the cell proliferation. Apoptotic morphology was observed by phase-contrast video microscopy and deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Sub-G1 DNA fragmentations and early apoptosis cells were assayed by flow cytometry (FCM) with propidium iodide (PI) staining and annexin V-FITC conjugated with PI staining. Apoptosis DNA ladders on agarose were observed. Activation of caspase-3 was assayed by FCM with FITC-conjugated monoclonal rabbit anti-active caspase-3 antibody and expressions of Bcl-2 and Bax proteins were examined immunocytochemically in 500 micromol/L-TC-induced apoptosis cells. RESULTS: Five bile salts except for GC, and two bile acids and the mixed bile salts could initiate growth inhibition of Eca109 cells in a dose- and time-dependent manner. TUNEL, FCM, and DNA ladder assays all demonstrated apoptosis induced by bile salts and bile acids at 500 micromol/L, except for GC. Early apoptosis cell percentages in Eca109 cells treated with GCDC, GDC, TC, TCDC, TDC, CA at 500 micromol/L for 12 h, DCA at 500 micromol/L for 6 h, and mixed bile salts at 1000 micromol/L for 12 h were 7.5%, 8.7%, 14.8%, 8.9%, 7.8%, 9.3%, 22.6% and 12.5%, respectively, all were significantly higher than that in control (1.9%). About 22% of the cell population treated with TC at 500 micromol/L for 24 h had detectable active caspase-3, and were higher than that in the control (1%). Immunocytochemical assay suggested that TC down-regulated Bcl-2 protein level and up-regulated Bax protein level. CONCLUSION: GCDC, GDC, TC, TCDC, TDC, CA and DCA, except for GC, can inhibit growth and induce apoptosis of esophageal cancer Eca109 cells. Activation of caspase-3, decreased Bcl-2 protein and increased Bax protein are involved in TC-induced apoptosis of Eca109 cells.

Apoptosis↗

PubMed1996

Altered bile acid metabolism related to atherosclerosis in alloxan diabetic rats.

Normal and alloxan diabetic rats were kept on a 0.25% cholesterol diet for 12 months and the changes in serum cholesterol levels, and fecal excretion of sterols and bile acids were examined to elucidate the influence of changes in bile acid metabolism on manifestations of hypercholesterolemia and development of atheromatous lesions. Diabetic rats fed the cholesterol diet showed increases in bile acid synthesis and in the cholic acid group/chenodeoxycholic acid group (CA/CDCA) ratio, and developed significant hypercholesterolemia and atheromatous lesions. In contrast, normal rats showed increased bile acids synthesis but a decreased CA/CDCA ratio after feeding with the cholesterol diet, and developed neither hypercholesterolemia nor atheromatous lesions. Fecal sterol excretion and the cholesterol/sitosterol ratio decreased in diabetic rats. Positive correlations were found between the cumulative serum cholesterol level and the atheromatous lesion area, and between the fecal CA/CDCA ratio and the serum cholesterol level, in the latter of which the correlation was higher in rats on the cholesterol diet than in those on the standard diet. These findings suggest that alteration of bile acid metabolism with increases in cholic acid synthesis and CA/CDCA ratio in diabetic rats enhances cholesterol absorption to produce significant hypercholesterolemia, which in turn leads to development of atheromatous lesions.

Alloxan↗