Role Of Bile Acids Research Articles

The Role of Bile Acids and Nitric Oxide in Apoptosis of Liver Cells

The Role of Bile Acids and Nitric Oxide in Apoptosis of Liver Cells

Chronic diarrhea

Chronic diarrhea

Bile acids induce cyclooxygenase-2 expression in human pancreatic cancer cell lines.

To investigate a possible link between bile acids and the pathogenesis of pancreatic cancer, we determined whether conjugated or unconjugated bile acids induced cyclooxygenase-2 (COX-2) in two human pancreatic cancer cell lines, BxPC-3 and SU 86.86. Bile acids are known promoters of gastric and colon cancer. We demonstrated previously that COX-2, an enzyme that catalyzes the synthesis of prostaglandins, is over-expressed in human pancreatic adenocarcinoma. Both human pancreatic cell lines were treated with conjugated and unconjugated bile acids. COX-2 mRNA and protein were determined. In addition, prostaglandin E2 (PGE2) synthesis was measured. Treatment with conjugated or unconjugated bile acids for 3 h up-regulated COX-2 mRNA. Chenodeoxycholate (CD) or deoxycholate at concentrations ranging from 12.5 to 100 micro M caused a dose-dependent induction of COX-2 protein with a maximal effect at 100 micro M. Induction of COX-2 protein by CD and deoxycholate was detected after treatment for 6 h with maximal induction at 12 h. Taurochenodeoxycholate, a conjugated bile acid, also caused dose-dependent induction of COX-2 but higher concentrations of bile acid (200-1200 micro M) were required. Levels of cyclooxygenase-1 were unaffected by bile acid treatment. Unconjugated and conjugated bile acids caused 7- and 4-fold increases in PGE2 production, respectively. Taken together, these findings suggest a possible role for bile acids in the pathogenesis of pancreatic cancer.

Barrett's esophagus: environmental influences in the progression of dysplasia.

Barrett's esophagus (BE) is composed of multiple lineages including Paneth cells and endocrine cells in addition to gastric and intestinal cells. Although the origin of the BE stem cell is a matter of conjecture, the stem cells are clearly multipotent, and therefore the phenotype is restricted by genomic imprinting (termed restricted potency). Recent evidence suggests that the microenvironment may select various lineages. In this regard the proportion of gastric and specialized intestinal metaplastic cells has been attributed to the composition of the refluxate, acid or bile, respectively. Experimental evidence also implicates specific xenobiotics in this process, including bile acids. In particular we discuss the potential biologic roles of bile acids in epithelial adaptation from in vivo and in vitro models.

Biliary atresia.

Biliary atresia.

The role of bile acids in carcinogenesis

Bile acids play a role in colorectal carcinogenesis as evidenced by epidemiological and experimental studies. Some bile acids stimulate growth of normal colonic and adenoma cells, but not of colorectal cancer cells. Moreover, bile acids stimulate invasion of colorectal cancer cells, at least in vitro. One possible mechanism of action is bile acid-induced DNA binding and transactivation of the activator protein-1 (AP-1) by co-operate activation of extracellular signal-regulated kinases (ERKs) and PKC signaling. In the present paper, we review the mechanisms by which bile acids influence carcinogenesis.

Role of bile acid and H.pylori in cholecystectomy patients

Role of bile acid and H.pylori in cholecystectomy patients

Role of bile acids and bile acid binding agents in patients with collagenous colitis

BACKGROUNDIn a retrospective study bile acid malabsorption was observed in patients with collagenous colitis.AIMSTo study the occurrence of bile acid malabsorption and the effect of bile acid binders prospectively in...

Comparison of the effects of bile acids on cell viability and DNA synthesis by rat hepatocytes in primary culture

Bile acid-induced inhibition of DNA synthesis by the regenerating rat liver in the absence of other manifestation of impairment in liver cell viability has been reported. Because in experiments carried out on in vivo models bile acids are rapidly taken up and secreted into bile, it is difficult to establish steady concentrations to which the hepatocytes are exposed. Thus, in this work, a dose–response study was carried out to investigate the in vitro cytotoxic effect of major unconjugated and tauro- (T) or glyco- (G) conjugated bile acids and to compare this as regards their ability to inhibit DNA synthesis. Viability of hepatocytes in primary culture was measured by Neutral red uptake and formazan formation after 6 h exposure of cells to bile acids. The rate of DNA synthesis was determined by radiolabeled thymidine incorporation into DNA. Incubation of hepatocytes with different bile acid species – cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), in the range of 10–1000 μM – revealed that toxicity was stronger for the unconjugated forms of CDCA and DCA than for CA and UDCA. Conjugation markedly reduced the effects of bile acids on cell viability. By contrast, the ability to inhibit radiolabeled thymidine incorporation into DNA was only slightly lower for taurodeoxycholic acid (TDCA) and glycodeoxycholic acid (GDCA) than for DCA. When the effect of these bile acids on DNA synthesis and cell viability was compared, a clear dissociation was observed. Radiolabeled thymidine incorporation into DNA was significantly decreased (−50%) at TDCA concentrations at which cell viability was not affected. Lack of a cause–effect relationship between both processes was further supported by the fact that well-known hepatoprotective compounds, such as tauroursodeoxycholic acid (TUDCA) and S-adenosylmethionine (SAMe) failed to prevent the effect of bile acids on DNA synthesis. In summary, our results indicate that bile acid-induced reduction of DNA synthesis does not require previous decreases in hepatocyte viability. This suggests the existence of a high sensitivity to bile acids of cellular mechanisms that may affect the rate of DNA repair and/or proliferation, which is of particular interest regarding the role of bile acids in the etiology of certain types of cancer.

Protective effects of butyric acid in colon cancer.

A great deal of evidence indicates that cancer is the result of a reciprocal interaction between genetic susceptibility and environmental factors. Apparently, only 5% of all cancers is linked to genetic, inheritable alterations, while the remainder is associated with environmental conditions that act in concert with individual susceptibility.1 In this context, dietary habit covers a fundamental role. Following the recent publication from the American Institute for Cancer Research2 (AICR), a “correct” diet could decrease the cancer rate by as much as 20%. For some specific cancers, the effect is even more dramatic: from 33 to 50% of breast cancer can be prevented through diet, and as much as 33% of lung cancer and 75% of colorectal cancers are prevented by correct diet choices. Colorectal cancer represents one of the well studied cancers at the molecular level: here, the steps of tumor progression show in vivo an accumulation of morphological changes that result in vivo in mutations in specific genes. Loss of function of the APC tumor suppressor gene causes hyperproliferation of normal epithelium and early adenoma; the subsequent activation of k-ras oncogene and inactivation of DCC and p53 tumor suppressor genes are associated with late adenoma and carcinoma.3,4 Colorectal cancers are very common causing over 50,000 deaths per year in the United States, 11% of total deaths from cancer. They result from the combined effect of inherited factors and stochastic genetic mutations, partially related to environmental conditions such as diet composition.5 Considerable epidemiological data support the hypothesis that a diet rich in fiber is associated with a decreased risk of intestinal cancers.6,7 Although this views appears simplistic and remains controversial for many aspects, it is currently generally accepted. In fact, one of the fifteen recommendations of the AICR advises to “eat a variety of vegetables and fruits all year round”.2 Several mechanisms have been considered in order to explain the protective effect of dietary fiber (DF). They include dilution of luminal carcinogen concentration, fiber-associated changes in colonic transit that decrease colonic enterocyte exposure to luminal carcinogens, interactions with intestinal contents, production of tissue factors by stimulation of colonic mucosa, role of bile acids and direct antineoplastic activity by DF components.8–13 A different mechanism by which fiber may modulate carcinogenesis is related to the production of butyric acid (BA), a component of the short-chain fatty acids (SFCA) obtained by degradation of poorly fermented fiber by colonic microflora. This review will focus on the molecular aspects that affect the activity of BA on in vivo and in vivo models.

Role of bile acids in duodenal migrating motor complexes in dogs.

Previous studies have suggested that enterohepatic circulation of bile acids is essential for regular cycling of duodenal migrating motor complexes (MMCs). The present study was an attempt to clarify the role of bile acids in the enterohepatic circulation system in initiating duodenal MMCs. Seven dogs underwent total external biliary diversion that resulted in the loss of MMCs originating from the duodenum. Sodium ursodeoxycholate (6 mg/kg/hr) was then given either through the portal vein or a peripheral vein, and motility of the gastrointestinal tract was serially recorded. When sodium ursodeoxycholate was given either through the portal vein or a peripheral vein during external biliary diversion, duodenal MMCs restarted. The cyclic change in plasma motilin levels during an MMC cycle as induced by sodium ursodeoxycholate was almost the same as in a normal MMC cycle. Total bile acid concentration in the portal vein changed cyclically with MMC cycles when bile flow was intact but did not change cyclically with MMC cycles restarted by intravenous bile salt infusion. Bile acid stimulation of putative receptors existing between the portal vein and intrahepatic bile ducts may be involved in initiating normal duodenal MMC cycles.

Elevated biliary calmodulin during gallstone formation: the role of bile acids.

Hepatic bile synthesis is altered during experimental gallstone formation. In response to cholesterol, there is a hydrophobic shift in hepatic bile acid synthesis and hypersecretion of phospholipids. These changes decrease the vesicular capacity for cholesterol and favor crystallization. The mechanism for these changes in hepatic bile formation is unknown. Calmodulin (CaM), a Ca2+ receptor protein involved in cellular secretion, regulates gallbladder transport and may play an important role in alterations of hepatic bile formation during cholelithiasis. We hypothesized that biliary CaM activity is altered during gallstone formation and may be associated with changes in bile acid and phospholipid synthesis. Prairie dogs were fed either control (N = 22) or 1.2% cholesterol-enriched (N = 26) diets for one to six weeks. Cholecystectomy was performed; the common bile duct was cannulated, and hourly bile samples were collected. CaM was measured in bile and gallbladder tissues by radioimmunoassay. Bile samples were analyzed for cholesterol, phospholipids, total bile acids, total protein, calcium, and individual bile acid composition. Compared to controls, gallstone animals had elevated hepatic bile levels of CaM, phospholipids, and cholesterol. Hydrophobic bile acid synthesis was also stimulated, with increased levels of taurochenodeoxycholic acid (TCDCA) and decreased taurocholic acid (TCA). Gallbladder bile demonstrated similar changes. Although gallbladder bile CaM levels were increased, tissue levels were unchanged, suggesting that increased CaM concentration is a hepatic phenomenon. Hepatic bile CaM activity correlated linearly with TCDCA concentration (r = 0.64, P < 0.004) and phospholipid hypersecretion (r = 0.53, P < 0.03). The relationship between biliary CaM and increased concentrations of TCDCA and phospholipids suggests a role for CaM in alterations of hepatocyte secretion that may promote gallstone formation.

Genotoxic activity in human faecal water and the role of bile acids: a study using the alkaline comet assay.

Human faecal waters from 35 healthy non-smoking volunteers (23 from England and 12 from Sweden) consuming their habitual diet were screened for genotoxicity by the single-cell gel electrophoresis (comet) assay using a human colon adenocarcinoma cell line (CACO-2) as the target. Hydrogen peroxide induced DNA damage was categorized as low, intermediate or high for tail moments greater than 5, 17 and 32, respectively: 11 samples were highly genotoxic, four were intermediate, one was low and 19 showed no activity. Endonuclease III treatment significantly increased DNA damage for all except the non-genotoxic faecal waters, suggesting that faecal water genotoxicity may be due, at least in part, to oxidative damage. Faecal water cytotoxicity has previously been attributed to the bile and fatty acid content. In the comet assay no DNA damage was induced by deoxycholate or lithocholate at normal physiological concentrations, suggesting that the genotoxicity of faecal water was due to other substances. Both bile acids induced DNA damage above 300 microM, levels often found in patients with colonic polyps and there was a significant increase in genotoxicity after endonuclease III treatment indicative of oxidative DNA damage.

Conjugated bile acids in breast cyst fluids: Relationship to cation-related cyst subpopulations

Gross cystic breast disease is a benign lesion occurring in 7% of adult women. Apocrine changes of epithelium lining the breast cysts cause a higher risk of developing breast cancer. According to the possible role of bile acids in the pathogenesis of cancer, we analysed breast cyst fluids aspirated from 96 women for distribution of conjugated bile acid concentrations in the two subsets of breast cysts. Bile acid levels were correlated to K + concentrations ( P < 0.0001) and mean value was higher in Na K < 3 metabolically active apocrine cyst as compared with Na K > 3 flattened cyst ( P < 0.001). Because bile acids could play an important role in the pathogenesis and growth of breast cancer, the significantly higher intracystic concentrations of these carcinogen compounds in apocrine Type I cysts might provide a further biological explanation as to why women with apocrine changes may be at higher breast cancer risk and could be useful for the biochemical knowledge occurring in the different functional stages of the gross breast cysts.

The effects of Bile Acids on Freshly Isolated Rat Glomeruli and Proximal Tubular Fragments

The role of bile acids in post-surgical acute renal failure in jaundiced patients is obscure. In this study the effects of 11 bile acids were assessed on freshly isolated rat glomeruli and proximal tubular fragments using de novo protein synthesis and lactate dehydrogenase (LDH) leakage as markers of cytotoxicity. Lithocholic acid inhibited protein synthesis from 5 μ m, chenodeoxycholic and deoxycholic acid from 50 μ m ( P<0.05). The concentration of hydrophobic bile acids that inhibited protein synthesis by 50% (IC 50) was 10 μ m, 75 μ m and 80 μ m for lithocholic, chenodeoxycholic and deoxycholic acids, respectively. The glycine and taurine conjugates of these bile acids had no significant effect on de novo protein synthesis up to 200 μ m. Lithocholic acid (50 μ m), chenodeoxycholic (200 μ m) and deoxycholic acids (200 μ m) caused a significant increase ( P<0.05) in LDH leakage. Lithocholic acid also directly inhibited LDH activity above 50 μ m ( P<0.05), whereas chenodeoxycholic acid and deoxycholic acid had no effect on LDH below 500 μ m, at which concentration they caused a slight increase in activity. The cytotoxic bile acids had no effect on the level of reactive oxygen species in kidney fragments. Hydrophobic bile acids inhibit protein synthesis and increase membrane permeability. Hydrophobic bile acids also directly alter LDH activity. Kidney cells are susceptible to the hydrophobic bile acids at concentration significantly below their critical micellar concentration. These results suggest that both glomeruli and tubules are highly sensitive to hydrophobic bile acids.

Acute and chronic effects of different bile acids on indomethacin-induced intestinal inflammation.

The role of bile acids in the pathogenesis of bowel inflammation is unknown. The objective of this study was to determine whether urso- (UDC), cheno- (CDC), and taurochenodeoxycholic acid (TCDC) exert a pro- or antiinflammatory action in the acute and chronic phase of the indomethacin model of a long lasting ileitis in rats. Short-term and long-term inflammatory responses (48 h and 10 days, respectively) after two subcutaneous indomethacin (Indo) injections were elicited in rat small bowel and mesentery. To distinguish between common and model-specific effects bile acids were tested also in another model of acute inflammation induced by mesenteric superfusion with leukotriene B4(LTB4). The number of adherent and emigrated leukocytes, leukocyte rolling velocity, and venular wall shear rate were monitored in normal and inflamed postcapillary venules, and fecal pH of ileal contents which has been shown to correlate with degree of inflammation was measured, 6.5- and 2.3-fold increases in leukocyte adherence and comparable increments in leukocyte emigration were observed 48 h and ten days after indomethacin treatment, respectively. UDC, CDC, and TCDC (10 mg/kg) given daily from Indo administration until the experiment attenuated the leukocyte adherence and emigration responses elicited by indomethacin in short- and long-term inflammation. This effect was accompanied by a significant increase of fecal pH which had been lowered by indomethacin. None of the bile acids reduced the LTB4-induced increases in adherence and emigration. Oral administration of UDC, CDC, and TCDC reduces leukocyte adhesion and emigration in acute and chronic stages of Indo-induced inflammation. This could be due to the alkalizing effect of these bile acids on fecal pH which has been shown to correlate with a decrease of leukocyte-endothelial cell interactions but--according to the missing effectiveness in another model of intestinal inflammation--not to specific influences on leukocyte-endothelial cell adhesion.

Stimulation of bile acid 6α-hydroxylation by rifampin

Background: Rifampin was shown to relieve pruritus in cholestatic liver diseases. There has been much speculation about the origin of pruritus, but it has not yet been comprehensively explained. The role of bile acids in producing pruritus is obscure and still under debate. Since rifampin both inhibits the uptake of bile acids into the hepatocyte and strongly induces mixed-function oxidases in the liver, the beneficial effects of this drug might be a consequence of altered bile acid metabolism. Methods: We investigated the influence of rifampin on urinary bile acid excretion with special respect to glucuronide and sulphate conjugates in 14 healthy volunteers before and after administration of rifampin, 600 mg×7 days, using each subject as his or her own control. Results: Bile acid glucuronide excretion increased from 0.55 to 1.19 μmol/24 h. This was in particular due to a significant increase of the urinary excretion of the 6α-hydroxylated hyocholic and hyodeoxycholic acids, the relative amounts of which accounted for about two thirds of the urinary bile acid excretion. Excretion of sulphates, however, decreased from 1.40 to 0.86 μmol/24 h due to a significantly reduced excretion of lithocholic acid sulphate. No changes in the excretion rates of other primary and secondary bile acids and no changes in their conjugation patterns were observed. Conclusions: The results provide evidence that rifampin induces 6α-hydroxylation of bile acids. The products are subsequently glucuronidated at the 6α-hydroxy groups, thus stimulating renal excretion of potentially toxic bile acids.

Role of bile acids in colorectal carcinogenesis.

Dietary factors are considered important environmental risk determinants for colorectal cancer development. Epidemiological studies have shown that a high fat (or meat) intake is associated positively and a high starch, fibre (non-starch polysaccharide), vegetable and fruit intake negatively with colorectal cancer incidence. One mechanism by which these effects are possibly exerted is through the metabolism of secondary bile acids. Secondary bile acids are formed after enzymatic deconjugation and dehydroxylation of primary bile acids in the large bowel by anaerobic bacteria. It has been shown that these compounds can have tumour-promoting capacities in animal experiments. In epidemiological studies, colonic cancer risk is related to the faecal bile acid concentration. In serum and bile of patients with colonic adenomas, more deoxycholic acid was detected than in healthy controls. Secondary bile acids are toxic to several cell systems at physiological concentrations. The exact mechanism by which these amphiphilic molecules exert their action is not well understood. It might act through membrane damage, intracellular mitochondrial action or genotoxic effects. So far the evidence that bile acids are involved in colonic carcinogenesis is largely circumstantial. It is, however, well accepted that environmental factors, such as dietary habits influence genetic susceptibility. Bile acids could play a promoting role in this process.

The role of bile acids on the plasma lipids in chicks given diets containing medium chain triacylglycerol

The role of bile acids on the plasma lipids in chicks given diets containing medium chain triacylglycerol

Bile cholesterol metastability is modulated by lecithin hydrophobicity: Unique role of bile acid in subselection of lecithin species

Bile cholesterol metastability is modulated by lecithin hydrophobicity: Unique role of bile acid in subselection of lecithin species